System and method for enhancing cardiac signal sensing by cardiac pacemakers through genetic treatment

ABSTRACT

The present invention provides delivery systems for and methods of delivering ion channel protein genetic material to cardiac cells in areas adjacent to where an electrode is to be positioned in a patient&#39;s heart to improve or correct the signal to noise ratio of cardiac signals, such as the P-wave. More specifically, there is provided a system and method for delivering sodium ion channel proteins or nucleic acid molecules encoding sodium ion channel proteins to a site in the heart adjacent to an electrode to increase the expression of the same, thereby enhancing the cardiac signal amplitude and enabling improved sensing of cardiac signals by an implanted pacemaker.

This application is a Continuation of application Ser. No. 09/514,907 filed Feb. 28, 2000 now U.S. Pat. No. 6,567,705, which is a continuation of application Ser. No. 08/682,433 filed Jul. 17, 1996 NOW ABANDONED.

FIELD OF THE INVENTION

The present invention relates to systems for and methods of genetically enhancing cardiac signals for use by cardiac pacemakers and, more particularly, for enhancing the signal to noise ratio of atrial P-waves for improved pacemaker sensing.

BACKGROUND OF THE INVENTION

The cardiac pacemaker is a widely used device for treating various cardiac disorders, e.g., sick sinus syndrome, “brady-tachy syndrome” and heart block. The basic function of the pacemaker is to deliver stimulus pulses to one or more of the patient's heart chambers, as and when needed, to initiate cardiac depolarizations and thus maintain a desired heart rate, or to affect improvements in cardiac output for patients in heart failure. In addition to delivering stimulus pulses, another important feature is the sensing of a patient's heartbeat signals, when they occur spontaneously, for purposes of controlling the stimulus pulse delivery. Thus, the demand pacemaker inhibits delivery of a stimulus pulse and resets the pulse generator in the event of sensing a timely spontaneous beat, i.e., a P-wave which is an atrial depolarization, or a QRS, or just R-wave, which is a ventricular depolarization. For example, an AAI mode pacemaker both paces and senses in just the atrium, and inhibits delivery of a pace pulse if a timely P-wave is sensed. The inhibit operation necessarily depends upon reliably sensing spontaneous P-waves. In a dual chamber pacemaker, both the P-wave and R-wave are sensed. As examples of dual chamber pacemakers, see U.S. Pat. Nos. 4,920,965; 4,539,991; and 4,554,921, incorporated herein by reference. A particular purpose of the dual chamber pacemaker may be to treat a block condition, where the patient's natural pacemaker is operating normally, causing timely atrial contractions, but the depolarization signal is not efficiently propagated to the ventricle so as to cause a following ventricular contraction. In such a situation, the dual chamber pacemaker is designed to sense the P-wave, and deliver a synchronized ventricular stimulus pulse, i.e., a pulse which stimulates the ventricle after a timed AV delay which approximates the AV delay of a healthy heart. It is seen that reliable sensing of the P-wave is vital to this type of dual chamber pacing.

In yet another type of pacemaker operation, the pacemaker operates in what is referred to a VDD mode, meaning that it paces only in the ventricle, but senses both P-waves and R-waves, i.e., has single chamber pacing but dual chamber sensing. The advantage of this mode is that only one lead need be positioned in the patient's heart, since no pacing pulses are delivered to the atrium. The VDD lead has the normal electrode or electrode pair at its distal end, for positioning in the ventricle; and it has a “floating” electrode (or electrode pair) proximal to the tip and positioned so that it is located in the atrium, for sensing the P-wave. See, for example, U.S. Pat. No. 5,127,694. However, since such a floating electrode is not necessarily embedded into or positioned adjacent the myocardium, the sensed P-wave is not as strong as for the case where a separate atrial lead is used, and consequently, the reliability of sensing the P-wave is even less.

Atrial sensing is additionally considered to be a significant problem because of the low P-wave amplitudes commonly available and the presence of relatively large far field QRS and other “noise” signals. It is commonly accepted that atrial P-wave amplitudes are relatively low compared to ventricular R-waves because of the differences in muscle mass near the electrodes. That is, ventricular R-waves are large because there is a large volume of myocardium around the electrode, whereas the atrial signal is small because the underlying tissue is relatively thin. Thus, for any pacing system which senses the P wave, such as an AAI pacer or any dual sense mode pacer, reliably sensing P-waves is a major problem for which improvement has long been sought.

With regard to the source of the P-wave, it is noted that it is not the muscle itself that is sensed, but the electric potentials resulting from the depolarization of several myocardial cells, i.e., a net positive ion flow into myocardial cells through specialized membrane proteins called voltage-gated ion channels, such as the sodium channels. More muscle mass means there are more membrane channels in the area adjacent to the electrodes. However, the muscle mass adjacent to the atrial electrode cannot be increased. But the P-wave could be enhanced if the number of conducting membrane channels within the adjacent muscle mass can be increased. Sodium channels are transmembrane proteins responsible for the rapid transport of Na⁺ ions across cell membranes underlying the depolarization of the action potential in many types of cells. In particular, cardiac fast sodium channels are responsible for the fast upstroke or phase 0 of the action potential in myocardial cells. Fozzard, et al., Circ. Res., 1985, 56, 475-485. Recently, a human cardiac voltage-dependent sodium channel, hH1, has been cloned, sequenced, and functionally expressed. Gellens, et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 554-558.

Gene therapy has also recently emerged as a powerful approach to treating a variety of mammalian diseases. Direct transfer of genetic material into myocardial tissue in vivo has recently been demonstrated to be an effective method of expressing a desired protein. For example, direct myocardial transfection of plasmid DNA by direct injection into the heart of rabbits and pigs (Gal, et al., Lab. Invest., 1993, 68, 18-25), as well as of rats (Acsadi, et al., The New Biol., 1991, 3, 71-81), has been shown to result in expression of particular reporter gene products. In addition, direct in vivo gene transfer into myocardial cells has also been accomplished by directly injecting adenoviral vectors into the myocardium. French, et al., Circulation, 1994, 90, 2415-2424, and PCT Publication WO 94/11506.

Pursuant to the above, this invention provides a system and method of enhancing the cardiac pacemaker atrial and/or ventricular sensing function, i.e., enhancing the signal to noise ratio of cardiac signals, and in particular the sensed P-wave, through concurrent genetic treatment whereby the number of ion channels responsible for depolarization of the atrial or ventricular myocardial cells is increased. Applicants' invention is directed to introducing ion channel protein genetic material into myocardial cells adjacent to or closest to the position of the atrial or ventricular electrode. In any particular application, the genetic material is placed so as to provide maximum benefit for sensing P-waves, or other cardiac signals, with the pacing lead used, i.e., for an AAI pacing system, a lead which is fixated against the atrial wall.

SUMMARY OF THE INVENTION

In accordance with the above, a primary purpose of Applicants' claimed invention is to provide methods and delivery systems for enhancing cardiac pacemaker signal sensing. In a particular embodiment, the claimed invention provides methods and delivery systems for enhancing cardiac pacemaker P-wave sensing. Upon identifying a patient in which the signal to noise ratio for atrial or ventricular sensing is problematic, ion channel protein genetic material is selected such that expression of a selected ion channel protein in cells adjacent to the position of the atrial or ventricle electrode corrects or improves the signal to noise ratio for cardiac signal sensing. Preferably, expression of a selected ion channel protein can improve or correct the signal to noise ratio for cardiac signal sensing in either or both the ventricles and atria of all persons with pacemakers, especially those persons which have been diagnosed with a low signal to noise ratio for P-wave sensing. Improvement or correction of P-wave sensing can be manifested by an increase in the amplitude of the P-wave, or other characteristic of the cardiac signal, thus resulting in an increase of the signal to noise ratio of the signal sensed in the pacemaker atrial sensing channel. Delivery of the ion channel protein genetic material can be accomplished by adaptation of available pacing leads, such as, for example, AAI or DDD leads, as well as by specific modification of leads and catheters. Delivery of the genetic material may be affected by a pump or may be passive.

The ion channel protein genetic material used in the system and method of this invention comprises recombinant nucleic acid molecules comprising a nucleic acid molecule encoding the ion channel protein inserted into a delivery vehicle, such as, for example, plasmids or adenoviral vectors, and the appropriate regulatory elements. Alternatively, the ion channel protein genetic material comprises the ion channel protein itself. Expression of the desired ion channel protein from recombinant nucleic acid molecules is controlled by promoters, preferably cardiac tissue-specific promoter-enhancers, operably linked to the nucleic acid molecule encoding the ion channel protein. The conduction protein is preferably a sodium ion channel protein, such as, for example, the voltage-dependent sodium channel hH1, which is used to correct or improve the signal to noise ratio of cardiac signals, and in particular, atrial P-wave sensing. The ion channel protein genetic material is delivered to specific sites adjacent to the atrial or ventricular electrode within the heart by perfusion or injection of a therapeutically effective amount, which is that amount which corrects or improves the signal to noise ratio of the cardiac signal of the myocardial cells adjacent to the electrode. The therapeutically effective amount can be delivered to the specific site in the heart in a single dose or multiple doses, as desired.

In carrying out the treatment provided by this invention, the patient's signal to noise ratio for a particular cardiac signal, such as, for example, P-wave sensing, is first studied to determine whether such cardiac signal sensing is adequate or, rather, whether the patient presents a condition requiring adjustment, which is addressable by genetically modifying the particular cardiac signal amplitude of myocardial cells adjacent the atrial or ventricular electrode in accordance with this invention. However, in a preferred embodiment, all patients with pacemakers may receive the treatment described herein to improve the cardiac signal sensing by their pacemakers. The appropriate ion channel protein genetic material is then selected, which step includes selection of the nucleic acid molecule encoding the ion channel protein, delivery vehicle, and the appropriate regulatory elements, etc., as noted above. It is also determined what dose is indicated for treating the problematic cardiac signal to noise ratio depending upon the extent of the noise that is diagnosed, and whether follow-up treatments require implantation of an externally controllable delivery system. The determined ion channel protein genetic material is prepared, and loaded into the delivery system. The treatment is then effected by utilizing the delivery system to deliver the therapeutic dose to the patient, e.g., either injecting the material or perfusing the selected area of the heart adjacent the atrial or ventricular electrode. After this genetic treatment, the patient is paced in a standard manner, e.g., AAI pacing or dual chamber synchronous pacing which includes sensing the patient's P-waves and delivering synchronized ventricular stimulus pulses, such as in the VDD or DDD mode.

The present invention further provides a delivery system for delivering a therapeutically effective amount of a predetermined ion channel protein genetic material to an identified cardiac location adjacent the atrial or ventricular electrode, the genetic material being selected for amplifying the particular cardiac signal, such as, for example, the P-wave, from cardiac cells to which it is delivered, thus improving or correcting the cardiac signal to noise ratio received by the sensing electrode. The delivery system includes the selected genetic material contained in a reservoir, and a catheter or electrode subsystem for delivering the genetic material from the reservoir to the identified cardiac location so as to contact a plurality of cells in the proximity of the sensing electrode.

The delivery system may utilize an external reservoir for providing the genetic material, or alternately may utilize an implantable reservoir. In either embodiment, a controllable pump mechanism may be provided for transferring therapeutic doses of the genetic material from the reservoir, through a catheter or electrode, and to the selected cardiac location. The pump may be a mini or micro pump located within the delivery system. Alternatively, rather than using a pump mechanism, the ion channel protein genetic material can be passively delivered to the appropriate location adjacent the appropriate electrode. The catheter subsystem may be of a type for direct introduction into the myocardium, as with a transthoracic procedure, or, more preferably, a endocardial catheter having a distal tip portion adapted for positioning and injecting the genetic material into the myocardium from within a heart chamber. In a preferred embodiment, the catheter distal tip has a normally withdrawn helical needle, which is extendable when positioned in the vicinity of the selected site so as to be screwed into the heart. The needle is hollow and connects with the catheter lumen so as to receive the pumped genetic material; it has one or more ports located so as to effectively release the genetic material for transduction into the cardiac area adjacent the sensing electrode. In the case of an electrode subsystem, an implantable electrode is used in place of the catheter subsystem, which is able to deliver drugs, such as steroids, or other bioactive agents, such as, for example, ion channel protein genetic material. Such implantable electrodes with drug dispensing capabilities are set forth in U.S. Pat. Nos. 4,711,251, 5,458,631, 4,360,031, and 5,496,360, each of which are incorporated herein by reference. The delivery system can be used for one treatment and then removed, or can be implanted for subsequent treatments, in which latter case it is controllable by an external programmer type device. In another embodiment, the catheter or electrode subsystem may be combined with a pacing lead for sensing the patient's cardiac signals and for providing stimulus pulses.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram presenting the primary steps involved in the practice of this invention, including selecting an appropriate genetic material, positioning delivery system against the heart wall, and expressing the genetic material in an appropriate dose into the determined location.

FIG. 2 is a schematic representation of a delivery system in accordance with this invention, illustrating delivery of genetic material into a patient's heart at the chosen location using a catheter subsystem.

FIG. 3 is a schematic drawing of the distal portion of a catheter which can be used for injecting a solution carrying chosen genetic material into a patient's heart.

FIG. 4 illustrates the distal end of a catheter, having a distal portion which encloses an osmotic pump.

FIG. 5A is a schematic representation of a delivery system in accordance with this invention, having a combined catheter and pacing lead, with a separate pump;

FIG. 5B is another embodiment of a combined pacing lead and delivery catheter having a reservoir located at the distal end of the catheter.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Applicants' invention provides methods and delivery systems for correcting or improving cardiac signal sensing, especially the signal to noise ratio of the atrial P-wave, thus enhancing pacemaker sensing. A problematic signal to noise ratio for P-waves results from a naturally low amplitude P-wave generated in the atrium, noise from the ventricular QRS complex, muscle noise, noise from other sources, or a combination thereof. The signal to noise ratio is determined by routine and conventional techniques known to the skilled artisan. Once the specific problem has been identified in a particular patient, e.g., in any patient with a pacemaker or who is to receive a pacemaker, ion channel protein genetic material is selected such that expression of a selected ion channel protein corrects or improves the cardiac signal amplitude, thus improving or correcting the cardiac signal to noise ratio. The ion channel protein genetic material comprises either the ion channel protein itself or recombinant nucleic acid molecules comprising a nucleic acid molecule encoding the ion channel protein inserted into a delivery vehicle, such as, for example, plasmid, cosmid, YAC vector, viral vectors, and the like, and the appropriate regulatory elements. In preferred embodiments of the present invention, the nucleic acid molecule encoding the ion channel protein is the full length coding sequence cDNA of an ion channel protein, and is inserted into a plasmid or adenoviral vector, such as, for example, pGEM3 or pBR322, and Ad5, respectively. The regulatory elements are capable of directing expression in mammalian cells, specifically human cells. The regulatory elements include a promoter and a polyadenylation signal. Expression of the desired ion channel protein is preferably controlled by cardiac tissue-specific promoter-enhancers, operably linked to the nucleic acid molecule encoding the ion channel protein. The ion channel protein is preferably a sodium channel protein, such as, for example, the hH1 voltage-regulated sodium channel, which is used to correct or improve the cardiac signal to noise ratio. The ion channel protein genetic material is preferably delivered in a pharmaceutical composition comprising, for example, the ion channel protein genetic material in a volume of phosphate-buffered saline with 5% sucrose. In some embodiments, the ion channel protein genetic material is delivered with genetic material encoding the Na⁺/K⁺ pump, which is also inserted into an appropriate delivery vehicle. The ion channel protein genetic material may also be delivered separately or in combination with class I and class IV antiarrhythmic drugs, which have been shown to increase sodium channel mRNA expression. The ion channel protein genetic material is delivered to specific sites within the heart, adjacent to the atrial or ventricular electrode, by perfusion or injection of a therapeutically effective amount, which is that amount which corrects or improves the cardiac signal to noise ratio. Preferably, the therapeutically effective amount corrects or improves the P-wave signal to noise ratio. The therapeutically effective amount can be delivered to the specific site in the heart in single or multiple doses, as desired, using the delivery systems of the invention.

The present invention also comprises a delivery system for delivering a therapeutically effective amount of ion channel protein genetic material to a specific cardiac location, adjacent the atrial or ventricular electrode, in such a way as to enhance the amplitude of the cardiac signal, thus improving or correcting the signal to noise ratio. In a first embodiment, the delivery system basically comprises a reservoir subsystem for holding the genetic material, and a catheter subsystem in communication with the reservoir subsystem for placement of the genetic material in and around the identified cardiac location. In another embodiment, the delivery system basically comprises a reservoir subsystem for holding the genetic material, and a electrode subsystem in communication with the reservoir subsystem for placement of the genetic material in and around the identified cardiac location. As seen in the following discussion of several preferred embodiments, the reservoir subsystem and catheter subsystem or electrode subsystem may be separate, or they may be combined. Preferably the reservoir contains up to 25 ml of a genetic material for delivery to the myocardium. In some applications, only a bolus of about 0.1-10 ml, or more preferably 1-5 ml, is delivered to the targeted areas. In other applications, such as where ion channel protein is being delivered in repeated doses, 25 ml or more may be used. Also, the genetic material may be diluted in a saline solution, such as, for example, phosphate-buffered saline (PBS), the reservoir holding the diluted solution for controlled delivery. Additionally, it is to be understood that the reservoir and associated control apparatus may be either implantable or external to the body, depending upon the circumstances, e.g., whether metered doses are to be administered to the patient over a period of time, or whether the delivery of the genetic material is essentially a one time treatment.

Referring now to FIG. 1, the primary steps involved in the practice of this invention are shown in the flow diagram. The illustrated steps are performed following the initial diagnosis of a patient with a problematic P-wave signal to noise ratio, which can result from a low amplitude P-wave generated in the atrium, noise from the ventricular QRS complex, noise from other sources, or a combination thereof. Diagnosis can be accomplished, for example, by electrocardiography procedures. Preferably, the steps are performed in connection with all patients having cardiac pacemakers. As illustrated in block 30, the next step is to select the appropriate ion channel protein genetic material. This selection yields the “preselected genetic material.” The ion channel protein genetic material is next prepared, as illustrated in block 31, by either inserting the nucleic acid molecules encoding the appropriate ion channel protein into a delivery vehicle with the appropriate regulatory elements, in the case of a recombinant nucleic acid molecule, or expressing the ion channel protein from an expression vector, in the case of the ion channel protein itself. As shown in block 32, the next step is to prepare and load the delivery system with a therapeutically effective amount of the ion channel protein genetic material. As illustrated in block 33, the next step comprises inserting the catheter, or other delivery subsystem, such as, for example, the electrode subsystem, into the patient's heart and positioning it against the heart wall. As shown in block 34, the next step comprises administering the therapeutically effective amount to the patient by contacting the appropriate location in the heart, adjacent to the atrial or ventricular electrode, using the delivery system described herein. An alternative method of administering the therapeutically effective amount of the ion channel protein genetic material is to directly inject the heart of the patient. The next step, shown in block 35, is to pace the patient in a standard manner, e.g., dual chamber synchronous pacing which includes sensing the patient's P-waves and delivering synchronized ventricular stimulus pulses, or AAI pacing. In accordance with this step, it may be preferable to adjust the sensitivity of the atrial or ventricular sensing channel in accordance with the observed cardiac signal amplitude. The final step 36, which is optional, is to evaluate the response of the patient to the treatment by, for example, measuring the amplitude of the cardiac signal, such as, for example, the P-wave, by conventional electrocardiographic techniques, such as, for example, by telemetry from the implanted pulse generator. The sensitivity can then be adjusted accordingly.

Referring now to FIG. 2, there is shown an illustrative embodiment of a delivery system useful for certain applications of this invention, e.g., where larger amounts of genetic material alone or in solution are employed. A catheter 38, preferably a transvenous catheter, includes an elongated catheter body 40, suitably an insulative outer sheath which may be made of polyurethane, Teflon, silicone, or any other acceptable biocompatible plastic. The catheter has a standard lumen (illustrated in FIG. 3) extending therethrough for the length thereof, which communicates through to a hollow helical needle element 44, which is adapted for screwing into the patient's myocardium. The outer distal end of helical element 44 is open or porous, thus permitting genetic material in fluid form to be dispensed out of the end, as is discussed in more detail below in connection with FIG. 3. At the proximal end of the catheter, a fitting 46 is located, to which a Luer lock 48 is coupled. Luer lock 48 is coupled to the proximal end of sheath 40 and receives the lumen. A swivel mount 50 is mounted to Luer lock 48, allowing rotation of the catheter relative to Luer lock 52. Luer lock 52 in turn is coupled through control element 54 to a tube 58 which communicates with reservoir 55, suitably through flow control 57 and filter 56. Reservoir 55 holds a supply of the selected genetic material. Control elements 57 and 54 are used for adjustment of the pressure and flow rate, and may be mechanically or electronically controlled. Thus, unit 54 or 57 may be used to control either rate of delivery, or dosage size, or both. Control unit 54 may be programmed to automatically release predetermined doses on a timed basis. Further, for an implanted system, control unit 54 may be activated from an external programmer as illustrated at 53. Reference is made to international application published under the PCT, International Publication No. WO 95/05781, incorporated herein by reference, for a more detailed description of such a reservoir and catheter combination. It is to be understood that such a system is useful for this invention primarily for applications where larger fluid amounts are to be expressed, e.g., where a diluted saline solution is used to wash or perfuse a selected area.

Referring now to FIG. 3, there is shown in expanded detail a schematic of the distal end of the catheter of FIG. 2, illustrating the interconnection of the helical element 44 with the interior of the catheter. As illustrated, the helical needle 44 is provided with an internal lumen 59 which is in communication with the internal lumen 63L of the lead formed by tube 63. In this embodiment, helical element 44 may also be a pacing electrode, in which case it is formed of conductive material and welded, or otherwise fastened, to tip element 61. Tip element 61 in turn is electrically connected to coil or coils 64, 65, which extend the length of the lead and are connected to a pacemaker. An outer membrane 60 forms the outer wall of elongated catheter body 40, shown in FIG. 2. Further referring to FIG. 3, element 44 has an outlet 75 where the genetic material may be expressed, and holes or ports 76, 77, and 78 may also be utilized for providing exits for the genetic material which is supplied through lumen 59 under a suitable pressure of zero up to about one atmosphere from reservoir 55 (shown in FIG. 2) and the control elements.

In practice, a catheter 38 of the form illustrated in FIGS. 2 and 3 is advanced to the desired site for treatment, eg, adjacent the site where the sensing electrode is to be positioned. The catheter may be guided to the indicated location by being passed down a steerable or guidable catheter having an accommodating lumen, for example as disclosed in U.S. Pat. No. 5,030,204; or by means of a fixed configuration guide catheter such as illustrated in U.S. Pat. No. 5,104,393. Alternately, the catheter may be advanced to the desired location within the heart by means of a deflectable stylet, as disclosed in PCT Patent Application WO 93/04724, published Mar. 18, 1993, or by a deflectable guide wire as disclosed in U.S. Pat. No. 5,060,660. In yet another embodiment, the helical element 44 may be ordinarily retracted within a sheath at the time of guiding the catheter into the patient's heart, and extended for screwing into the heart by use of a stylet. Such extensible helical arrangements are well known in the pacing art, and are commercially available.

It is to be understood that other forms of the reservoir subsystems and catheter subsystems are within the scope of this invention. Reservoir embodiments include, for example, drug dispensing irrigatable electrodes, such as those described in U.S. Pat. No. 4,360,031; electrically controllable, non-occluding, body implanting drug delivery system, such as those described in U.S. Pat. No. 5,041,107; implantable drug infusion reservoir such as those described in U.S. Pat. No. 5,176,641; medication delivery devices such as those described in U.S. Pat. No. 5,443,450; infusion pumps, such as SYNCHROMED® made by Medtronic, Inc.; and osmotic pumps, such as those made by Alza.

Referring now to FIG. 4, there is shown, by way of illustration, another embodiment of a delivery system having a combined catheter and reservoir, useful for applications involving delivery of a relatively small bolus of genetic material, e.g., 1-5 ml. FIG. 4 illustrates the distal end of a catheter, having a distal portion 70 which encloses an osmotic pump. See U.S. Pat. No. 4,711,251, assigned to Medtronic, Inc., incorporated herein by reference. The pump includes an inner chamber 68 and an outer chamber 66, which chambers are separated by an impermeable membrane 67. A semi-permeable outer membrane 72 forms the outer wall of chamber 66. The tubular portion 74 of the helical member connects to lumen 74L within inner chamber 68. A conductor 80, which runs the length of the catheter, extends into the inner chamber 68 and connects with extension 74E as shown at 74C to provide electrical contact through to element 44, in an application which the element 44 is used as a pacing electrode. A insulating cover 86 encompasses the conductor 80 from the point of contact with the semi-permeable outer membrane 72 distally. A seal 79 is provided at the point where the conductor passes through outer membrane 72 and inner membrane 67. An end cap 73, which may be integral with outer membrane 72 closes the chamber. Alternately, end cap 73 may be constructed to elute a predetermined medication, such as, for example, steroids. Steroids, such as dexamethasone sodium phosphate, beclamethasone, and the like, are used to control inflammatory processes.

In this arrangement, prior to inserting the catheter distal end into the patient's heart, the inner chamber 68 is charged with the genetic material which is to be dispensed into the myocardium. This may be done, for example, by simply inserting a micro needle through end cap 73, and inserting the desired bolus of genetic material into chamber 68. After the chamber 68 is filled and the is catheter is implanted, body fluids will enter chamber 66 through membrane 72 to impart a pressure on the inner chamber 68 via the impermeable membrane 67. This results in a dispensing of the genetic material stored within chamber 68 through the lumen 74L of extension 74E and through the outlet 75 of the helical element 44. Although the preferred needle or element 44 is helical, additional configurations of needles or elements can also be used as known to those skilled in the art.

Still referring now to FIG. 4, there is illustrated another embodiment of a catheter tip useful for delivering a small bolus of the selected genetic material. In this embodiment, the bolus of material is stored within the hollow interior of distal needle 44, i.e., the interior is the reservoir. The interior reservoir is maintained sealed by use of a soluble material which is normally solid, but which dissolves when subjected to body fluids for a period of time. An example of such material is mannitol. Plugs or globules 81-85 of mannitol are illustrated (by dashed lines) in place to block the two ends of element 44, as well as the ports 76, 77, 78. This may be combined with an osmotic pump, as described in connection with FIG. 3, where the outer chamber is filled with a saline solution which forces the genetic material out of the ports of element 44. Another alternate embodiment, not shown, is to use a stylet which inserted through to the distal end of the catheter, to push a piston which aids in expressing the genetic material into the myocardial cells. Alternatively, the piston can be driven by a micro pump. In another embodiment, the genetic material contacts the myocardial cells by passive delivery.

Referring now to FIG. 5A, there is shown, by way of illustration, another embodiment of an implantable delivery system comprising a combined pacing lead and delivery catheter, hereinafter referred to simply as a catheter. In this embodiment, the catheter 90 is combined with a pacemaker or pulse generator (not shown) and a source of genetic material such as illustrated by pump 92 which is suitably implanted near the pacemaker. The proximal end 91 of the catheter is connected to the pacemaker in the standard fashion. The genetic material is delivered through connecting tube 93 to a proximal section 88 of the catheter, communicating with lengthwise catheter lumen illustrated at 89. Alternately, the pacemaker head may contain a reservoir and micropump, for providing delivery of the genetic material directly to the lumen 89. The main length of the catheter has an outside sheath of biocompatible insulating material 96, and at least one conductor coil 95 which communicates electrically from the pacemaker to electrode 97 at the distal tip of the catheter. The catheter further comprises an axially positioned polymeric cannula 94, having lumen 87, through at least a portion of the catheter length and positioned within coil 95, which provides an inner surface for the catheter lumen. The cannula terminates at the distal end of the catheter, just proximal to the tip portion of electrode 97, which is illustrated as having an outer porous surface. Electrode 97 has a central opening, shown covered with the porous electrode material, through which genetic material can pass when the catheter is positioned in the patient. As shown, conductor coil 95 is electrically connected to electrode 97, and connects pace pulses and sensed cardiac signals between the pacemaker and the electrode. Of course, for a bipolar embodiment, the lead/catheter 90 carries a second electrode (not shown), suitably a ring electrode just proximal to electrode 97. Also, as illustrated, a fixation mechanism such as tines 98 are employed for fixing or anchoring the distal tip to the heart wall of the patient.

In one embodiment, pump 92 is suitably an osmotic minipump, which pumps fluid contained within through tube 93, into catheter portion 88 and through the lumens 89, 87 to the tip electrode 97. As mentioned previously, the reservoir and pump may alternately be mounted in the pacemaker device itself. In either instance, the genetic material is delivered under very minimal pressure from the reservoir through the lumen of the catheter to the electrode, where it is passed through the electrode central channel to contact myocardial cells. In yet another embodiment, the lumen portion 87 provided by the cannula is utilized as the reservoir. In this embodiment, delivery may either be passive, or with the aid of a micropump (not shown). The genetic material can be preloaded into the cannula, or it can be inserted by a needle just before the catheter is introduced and positioned with the patient.

In another embodiment, as illustrated in FIG. 5B, a chamber 99 is provided just proximal from eluting electrode 97, and serves as the reservoir of the genetic material. Insulating material 96 is formed from a self-sealing material such that it may be pierced with a needle, or the like, and reseal itself, thus allowing introduction of the genetic material into the chamber prior to implantation. Alternately, insulating material 96 can contain a port (not shown) through which the needle inserts the genetic material. In this embodiment, delivery of the material is without a pump, i.e., passive, the material draining slowly through the microporous portion of electrode 97.

The above described delivery systems can be used, for example, in methods of pacing and enhancing the detectability of sensed cardiac signals. A supply of a genetic material of the class having the property of increasing the expression of ion channels in cardiac cells to which it is delivered is selected. A transvenous catheter, having proximal and distal ends and a pacing electrode at the distal end, is introduced into the patient. The distal end of the catheter is positioned against the patient's heart wall and the genetic material is delivered through the catheter and out of the distal end, to the cardiac cells adjacent the pacing electrode, thereby enhancing cardiac signals produced by the cells. Normal cardiac pacing is carried out with the pacemaker and connected catheter implanted in the patient.

Although a transvenous form of delivery system is preferred, it is to be understood that the invention can employ other methods and devices. For example, a small bolus of selected genetic material can be loaded into a micro-syringe, e.g., a 100 μl Hamilton syringe, and applied directly from the outside of the heart.

As used herein, the phrase “cardiac signal” refers to any cardiac signal that is detectable and includes, but is not limited to, the P-wave.

As used herein, the phrase “signal to noise ratio” refers to the ratio of the amplitude of the cardiac signal, such as, for example, the P-wave, to the amplitude of the “noise.” In addition, the signal to noise ratio can be measured for other cardiac signals as well. Sources of “noise” include, but are not limited to, the QRS complex and muscle noise. It is desirable to establish a high signal to noise ratio, i.e., a signal to noise ratio of greater than 1:1 for unipolar leads and greater than 3:1 for bipolar leads. It is even more preferred to establish a signal to noise ratio greater than 10:1.

As used herein, the phrase “ion channel protein genetic material” refers to recombinant nucleic acid molecules encoding an ion channel protein or, alternatively, an ion channel protein itself, which is used in the methods and delivery systems of the invention. For chronic treatment, or long term treatment, the ion channel protein genetic material will be in the form of recombinant nucleic acid molecules encoding the ion channel protein. In contrast, for acute treatment, or short term treatment, the ion channel protein genetic material will be in the form of the ion channel proteins themselves.

A “recombinant nucleic acid molecule”, as used herein, is comprised of an isolated ion channel protein-encoding nucleotide sequence inserted into a delivery vehicle. Regulatory elements, such as the promoter and polyadenylation signal, are operably linked to the nucleotide sequence encoding the ion channel protein, whereby the protein is capable of being produced when the recombinant nucleic acid molecule is introduced into a cell.

The nucleic acid molecules encoding the ion channel proteins are prepared synthetically or, preferably, from isolated nucleic acid molecules, as described below. A nucleic acid is “isolated” when purified away from other cellular constituents, such as, for example, other cellular nucleic acids or proteins, by standard techniques known to those of ordinary skill in the art. The coding region of the nucleic acid molecule encoding the ion channel protein can encode a full length gene product or a subfragment thereof, or a novel mutated or fusion sequence. The protein coding sequence can be a sequence endogenous to the target cell, or exogenous to the target cell. The promoter, with which the coding sequence is operably associated, may or may not be one that normally is associated with the coding sequence.

The nucleic acid molecule encoding the ion channel protein is inserted into an appropriate delivery vehicle, such as, for example, an expression plasmid, cosmid, YAC vector, and the like. Almost any delivery vehicle can be used for introducing nucleic acids into the cardiovascular system, including, for example, recombinant vectors, such as one based on adenovirus serotype 5, Ad5, as set forth in French, et al., Circulation, 1994, 90, 2414-2424, which is incorporated herein by reference. An additional protocol for adenovirus-mediated gene transfer to cardiac cells is set forth in WO 94/11506, Johns, J. Clin. Invest., 1995, 96, 1152-1158, and in Barr, et al., Gene Ther., 1994, 1, 51-58, both of which are incorporated herein by reference. Other recombinant vectors include, for example, plasmid DNA vectors, such as one derived from pGEM3 or pBR322, as set forth in Acsadi, et al., The New Biol., 1991, 3, 71-81, and Gal, et al., Lab. Invest., 1993, 68, 18-25, both of which are incorporated herein by reference, cDNA-containing liposomes, artificial viruses, nanoparticles, and the like. It is also contemplated that ion channel proteins be injected directly into the myocardium.

The regulatory elements of the recombinant nucleic acid molecules of the invention are capable of directing expression in mammalian cells, specifically human cells. The regulatory elements include a promoter and a polyadenylation signal. In addition, other elements, such as a Kozak region, may also be included in the recombinant nucleic acid molecule. Examples of polyadenylation signals useful to practice the present invention include, but are not limited to, SV40 polyadenylation signals and LTR polyadenylation signals. In particular, the SV40 polyadenylation signal which is in pCEP4 plasmid (Invitrogen, San Diego, Calif.), referred to as the SV40 polyadenylation signal, can be used.

The promoters useful in constructing the recombinant nucleic acid molecules of the invention may be constitutive or inducible. A constitutive promoter is expressed under all conditions of cell growth. Exemplary constitutive promoters include the promoters for the following genes: hypoxanthine phosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase, β-actin, human myosin, human hemoglobin, human muscle creatine, and others. In addition, many viral promoters function constitutively in eukaryotic cells, and include, but are not limited to, the early and late promoters of SV40, the Mouse Mammary Tumor Virus (MMTV) promoter, the long terminal repeats (LTRs) of Maloney leukemia virus, Human Immunodeficiency Virus (HIV), Cytomegalovirus (CMV) immediate early promoter, Epstein Barr Virus (EBV), Rous Sarcoma Virus (RSV), and other retroviruses, and the thymidine kinase promoter of herpes simplex virus. Other promoters are known to those of ordinary skill in the art.

Inducible promoters are expressed in the presence of an inducing agent. For example, the metallothionein promoter is induced to promote (increase) transcription in the presence of certain metal ions. Other inducible promoters are known to those of ordinary skill in the art.

Promoters and polyadenylation signals used must be functional within the cells of the mammal. In order to maximize protein production, regulatory sequences may be selected which are well suited for gene expression in the cardiac cells into which the recombinant nucleic acid molecule is administered. For example, the promoter is preferably a cardiac tissue-specific promoter-enhancer, such as, for example, cardiac isoform troponin C (cTNC) promoter. Parmacek, et al., J. Biol. Chem., 1990, 265, 15970-15976, and Parmacek, et al., Mol. Cell Biol., 1992, 12, 1967-1976. In addition, codons may be selected which are most efficiently transcribed in the cell. One having ordinary skill in the art can produce recombinant nucleic acid molecules which are functional in the cardiac cells.

Genetic material can be introduced into a cell or “contacted” by a cell by, for example, transfection or transduction procedures. Transfection refers to the acquisition by a cell of new genetic material by incorporation of added nucleic acid molecules. Transfection can occur by physical or chemical methods. Many transfection techniques are known to those of ordinary skill in the art including: calcium phosphate DNA co-precipitation; DEAE-dextran DNA transfection; electroporation; naked plasmid adsorption, and cationic liposome-mediated transfection. Transduction refers to the process of transferring nucleic acid into a cell using a DNA or RNA virus. Suitable viral vectors for use as transducing agents include, but are not limited to, retroviral vectors, adeno associated viral vectors, vaccinia viruses, and Semliki Forest virus vectors.

Treatment of cells, or contacting cells, with recombinant nucleic acid molecules can take place in vivo or ex vivo. For ex vivo treatment, cells are isolated from an animal (preferably a human), transformed (i.e., transduced or transfected in vitro) with a delivery vehicle containing a nucleic acid molecule encoding an ion channel protein, and then administered to a recipient. Procedures for removing cells from mammals are well known to those of ordinary skill in the art. In addition to cells, tissue or the whole or, parts of organs may be removed, treated ex vivo and then returned to the patient. Thus, cells, tissue or organs may be cultured, bathed, perfused and the like under conditions for introducing the recombinant nucleic acid molecules of the invention into the desired cells.

For in vivo treatment, cells of an animal, preferably a mammal and most preferably a human, are transformed in vivo with a recombinant nucleic acid molecule of the invention. The in vivo treatment may involve systemic intravenous treatment with a recombinant nucleic acid molecule, local internal treatment with a recombinant nucleic acid molecule, such as by localized perfusion or topical treatment, and the like. When performing in vivo administration of the recombinant nucleic acid molecule, the preferred delivery vehicles are based on noncytopathic eukaryotic viruses in which nonessential or complementable genes have been replaced with the nucleic acid sequence of interest. Such noncytopathic viruses include retroviruses, the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have recently been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell line with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in Kriegler, M. “Gene Transfer and Expression, a Laboratory Manual”, W. H. Freeman Co., New York (1990) and Murry, E. J. e.d. “Methods in Molecular Biology”, Vol. 7, Humana Press, Inc., Clifton, N.J. (1991).

A preferred virus for contacting cells in certain applications, such as in in vivo applications, is the adeno-associated virus, a double-stranded DNA virus. The adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as heat and lipid solvent stability, high transduction frequencies in cells of diverse lineages, including hemopoietic cells, and lack of superinfection inhibition thus allowing multiple series of transductions. Recent reports indicate that the adeno-associated virus can also function in an extrachromosomal fashion.

In preferred embodiments of the present invention, the recombinant nucleic acid molecules comprising nucleic acid molecules encoding the ion channel proteins, or, in the alternative, the ion channel proteins, are delivered to cardiac cells adjacent the atrial or ventricular electrode, or both, using the delivery systems set forth above. Alternatively, the ion channel protein genetic material is delivered to the cardiac cells by direct injection.

In preferred embodiments of the present invention, the nucleic acid molecules encoding the ion channel proteins comprise the full length coding sequence cDNA of an ion channel protein. Preferably, the ion channel proteins are sodium channel proteins; more preferably, the ion channel protein is the voltage-regulated sodium channel hH1. Such a nucleic acid molecule is described in the Gellens, et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 554-558, and White, et al., Mol. Pharmacol., 1991, 39, 604-608 references, both of which are incorporated herein by reference, which contain the full length amino acid sequence and cDNA sequence, respectively.

Introduction of the ion channel-encoding nucleic acid molecules or the ion channel proteins to cardiac cells adjacent the atrial or ventricular electrode will result in increased expression of sodium channels, producing a larger cardiac signal, such as, for example, P-wave, and thus, an improved or corrected signal to noise ratio,

Nucleic acid molecules comprising nucleotide sequences encoding hH1 sodium channel are isolated and purified according to the methods set forth in Gellens, et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 554-558, and White, et al., Mol. Pharmacol., 1991, 39, 604-608. The nucleic acid and protein sequences of hH1 sodium channel are set forth in SEQ ID NO:1 and SEQ ID NO:2, respectively. It is contemplated that nucleic acid molecules comprising nucleotide sequences that are preferably at least 70% homologous, more preferably at least 80% homologous, and most preferably at least 90% homologous to the ion channel nucleotide sequences described in SEQ ID NO:1 can also be used.

It is understood that minor modifications of nucleotide sequence or the primary amino acid sequence may result in proteins which have substantially equivalent or enhanced activity as compared to the ion channel proteins exemplified herein. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental such as through mutations in hosts which produce the ion channel proteins. A “mutation” in a protein alters its primary structure (relative to the commonly occurring or specifically described protein) due to changes in the nucleotide sequence of the DNA which encodes it. These mutations specifically include allelic variants. Mutational changes in the primary structure of a protein can result from deletions, additions, or substitutions. A “deletion” is defined as a polypeptide in which one or more internal amino acid residues are absent as compared to the native sequence. An “addition” is defined as a polypeptide which has one or more additional internal amino acid residues as compared to the wild type protein. A “substitution” results from the replacement of one or more amino acid residues by other residues. A protein “fragment” is a polypeptide consisting of a primary amino acid sequence which is identical to a portion of the primary sequence of the protein to which the polypeptide is related.

Preferred “substitutions” are those which are conservative, i.e., wherein a residue is replaced by another of the same general type. As is well understood, naturally-occurring amino acids can be subclassified as acidic, basic, neutral and polar, or neutral and nonpolar and/or aromatic. It is generally preferred-that encoded peptides differing from the native form contain substituted codons for amino acids which are from the same group as that of the amino acid replaced. Thus, in general, the basic amino acids Lys, Arg, and Histidine are interchangeable; the acidic amino acids Asp and Glu are interchangeable; the neutral polar amino acids Ser, Thr, Cys, Gln, and Asn are interchangeable; the nonpolar aliphatic acids Gly, Ala, Val, Ile, and Leu are conservative with respect to each other (but because of size, Gly and Ala are more closely related and Val, Ile and Leu are more closely related), and the aromatic amino acids Phe, Trp, and Tyr are interchangeable.

While Pro is a nonpolar neutral amino acid, it represents difficulties because of its effects on conformation, and substitutions by or for Pro are not preferred, except when the same or similar conformational results can be obtained. Polar amino acids which represent conservative changes include Ser, Thr, Gln, Asn; and to a lesser extent, Met. In addition, although classified in different categories, Ala, Gly, and Ser seem to be interchangeable, and Cys additionally fits into this group, or may be classified with the polar neutral amino acids. Some substitutions by codons for amino acids from different classes may also be useful.

Once the nucleic acid molecules encoding the ion channel proteins are isolated and purified according to the methods described above, recombinant nucleic acid molecules are prepared in which the desired ion channel nucleic acid molecule is incorporated into a delivery vehicle by methods known to those skilled in the art, as taught in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. Cold Spring Harbor Press (1989). Preferred delivery vehicles include, for example, plasmids (Acsadi, et al., The New Biol., 1991, 3, 71-81, and Gal, et al., Lab. Invest., 1993, 68, 18-25, both of which are incorporated herein by reference) and adenovirus (WO 94/11506, Johns, J. Clin. Invest., 1995, 96, 1152-1158, and in Barr, et al., Gene Ther., 1994, 1, 51-58, each of which are incorporated herein by reference). The nucleic acid molecules encoding ion channel proteins, or ion channel proteins produced therefrom, are delivered to the cardiac cells adjacent to the atrial electrode by the delivery systems of the present invention. Thus, such delivery systems of the present invention are used to contact the cardiac cells adjacent the atrial electrode with recombinant nucleic acid molecules encoding an ion channel protein, or ion channel proteins.

Where the ion channel protein genetic material is in the form of ion channel proteins, such proteins can be prepared in large quantities by using various standard expression systems known to those skilled in the art. Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. Cold Spring Harbor Press (1989), pp. 16.1-16.55, incorporated herein by reference.

The recombinant nucleic acid molecules or ion channel proteins are preferably delivered in a pharmaceutical composition. Such pharmaceutical compositions can include, for example, the recombinant nucleic acid molecule or protein in a volume of phosphate-buffered saline with 5% sucrose. In other embodiments of the invention, the recombinant nucleic acid molecule or protein is delivered with suitable pharmaceutical carriers, such as those described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. The recombinant nucleic acid molecule or protein is delivered in a therapeutically effective amount. Such amount is determined experimentally and is that amount which either improves or corrects the P-wave signal to noise ratio by enhancing the P-wave amplitude as a result of the increased expression of sodium channels in the cardiac cells adjacent the atrial or ventricular electrode. The amount of recombinant nucleic acid molecule or protein is preferably between 0.01 μg and 100 mg, more preferably between 0.1 kg and 10 mg, more preferably between 1 μg and 1 mg, and most preferably between 10 μg and 100 μg. A single therapeutically effective amount is referred to as a bolus. Where adenovirus vectors are used, the amount of recombinant nucleic acid molecule is preferably between 10⁷ plaque forming units (pfu) and 10¹⁵ pfu, more preferably between 10⁸ pfu and 10¹⁴ pfu, and most preferably between 10⁹ pfu and 10¹² pfu. A single therapeutically effective amount of ion channel protein genetic material is referred to as a bolus. In some embodiments of the present invention, the delivery of the recombinant nucleic acid molecules or proteins is combined with steroid elution, such as with dexamethasone sodium phosphate, beclamethasone, and the like, to control inflammatory processes.

In some embodiments of the invention, it may be preferred to administer, in addition to ion channel protein genetic material, delivery vehicle encoding the Na⁺/K⁺ pump. The Na⁺/K⁺ pump acts to discharge Na⁺ ions from the myocardial cells that have accumulated as a result of the introduction of the ion channel protein genetic material. This treatment can be optional, as determined by the skilled practitioner. cDNA encoding the alpha and beta subunits of the human Na⁺/K⁺ pump are set forth in Kawakami, et al., J. Biochem., 1986, 100, 389-397, and Kawakami, et al., Nuc. Acids Res., 1986, 14, 2833-2844, both of which are incorporated herein by reference, The nucleic acid and amino acid sequences for the alpha subunit are set forth in SEQ ID NO:5 and SEQ ID NO:6, respectively. The nucleic acid and amino acid sequences for the beta subunit are set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively. The delivery vehicles for the pump subunits can be constructed from cDNA libraries in the same manner as set forth for hH1, except that the forward primer 5′-ATGGGGAAGGGGGTTGGACGTGAT-3′ (SEQ ID NO:9) and reverse primer 5′-ATAGTAGGTTTCCTTCTCCACCCA-3′ (SEQ ID NO:10) for the alpha subunit, and the forward primer 5′-ATGGCCCGCGGGAAAGCCAAGGAG-3′ (SEQ ID NO:11)and reverse primer 5′-GCTCTTAACTTCAATTTTTACATC-3′ (SEQ ID NO:12) for the beta subunit are used. It is understood that other primers can be used in addition to those set forth herein, as is well known to the skilled artisan, A therapeutically effective amount of the genetic material encoding the Na⁺/K⁺ pump is delivered to the myocardial cells using the delivery systems described herein. The therapeutically effective amount is determined by the practitioner, and depends upon the results achieved with the ion channel protein genetic material.

In preferred embodiments of the invention, the recombinant nucleic acid molecules encoding the ion channel proteins is delivered with class I and/or class IV antiarrhythmic drugs, such as, for example, verapamil, mexiletine, and the like, or combinations thereof. These drugs may be delivered subcutaneously, intravenously, injected in the immediate vicinity of the atrial electrode, or as determined by the skilled artisan. These drugs may be delivered by one injection, or in multiple injections. The amount of antiarrhythmic drugs depends upon the age, weight, sex, and other characteristics of the patient, and is determined empirically by the skilled artisan. Class I and/or class IV antiarrhythmic drugs have been shown to enhance sodium ion channel expression in mammals. Duff, et al., Mol. Pharmacol., 1992, 42, 570-574, and Taouis, et al., J. Clin. Invest., 1991, 88, 375-378, both of which are incorporated herein by reference.

The following examples are meant to be exemplary of the preferred embodiments of the invention and are not meant to be limiting.

EXAMPLES Example 1

Isolation and Purification of Nucleic Acid Molecule Encoding hH1

Nucleic acid molecules encoding hH1 are isolated and purified according to general methods well known to those skilled in the art, and in particular, by the method set forth in Gellens, et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 554-558, incorporated herein by reference. Briefly, a size selected and random-primed adult human cardiac cDNA library constructed in λZAPII (Stratagene) is screened with cDNA probes corresponding to nucleotides 1-4385 and 5424-7076 derived from the rat muscle TTX-I isoform (rSkM2), as set forth in Kallen, et al., Neuron, 1990, 4, 233-242, incorporated herein by reference. Hybridizations are performed at 42° C. for 18 hours in 50% formamide, 5×SSPE, 5×Denhardt's solution, 0.1% SDS/salmon sperm DNA, random primed ³²P-labeled probe. Filters are washed with 6×standard saline citrate, 0.10% SDS at 65° C. Plaque purified clones are rescued as pBluescript phagemids and sequenced as described in Kallen, et al., Neuron, 1990, 4, 233-242. A full-length hH1 construct is made in peluescript by sequential ligation of S14 EcoR1-Sac II (nt+1 to +252), C75 Sac II-KpnI (nt +253 to +4377), and C92 KpnI-EcoR1 (nt +4378 to +8491) fragments and the full length insert is moved into a modified pSP64T vector, as set forth in White, et al., Mol. Pharmacol., 1991, 39, 604-608, incorporated herein by reference. Nucleotides −151 to −8 of the 5′ untranslated region are deleted from the construct using exonuclease III and mung bean nuclease, as set forth in White, et al., Mol. Pharmacol., 1991, 39, 604-608.

Alternatively, cDNA for hH1 may be prepared from fresh cardiac tissue. Briefly, total cellular RNA is isolated and purified (Chomczynsky, et al., Anal. Biochem., 1987, 162, 156-159) from heart tissue, obtained from cardiac transplantation donors, or from salvaged tissue, and selected for poly(A) RNA (Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. Cold Spring Harbor Press (1989), pp. 7.26-7.29). cDNA corresponding to the hH1 sodium channel protein is prepared from the poly(A) cardiac RNA by reverse transcription using a GENEAMP™ PCR kit (Perkin Elmer Cetus, Norwalk, Conn.), or the like, using random hexamers according to the manufacturer's instructions. The specific hH1 nucleic acid molecules are amplified by the polymerase chain reaction (PCR), also using the GENEAMP™ PCR kit, or the like, using forward and reverse primers specific for hH1 according to the manufacturer's instructions. For example, the forward primer for cloning hH1 is preferably 5′-ATGGCAAACTTCCTATTACCTCGG-3′ (SEQ ID NO:3), and the reverse primer is 5′-CACGATGGACTCACGGTCCCTGTC-3′ (SEQ ID NO:4). It is understood that additional primers can be used for amplification as determined by those skilled in the art. These primers may be preceded at the 5′ terminus by nucleotide sequences containing endonuclease restriction sites for easy incorporation into vectors. The specific ion channel nucleic acid molecules can also be amplified by PCR from human genomic DNA (Stratagene, San Diego, Calif.) After cutting the PCR products with the appropriate restriction endonuclease(s), the PCR products are purified by phenol:chloroform extractions, or using commercial purification kits, such as, for example, MAGIC™ Minipreps DNA Purification System (Promega, Madison, Wis.). The specific nucleotide sequence of the PCR products is determined by conventional DNA sequencing procedures, and the identity of the PCR products confirmed by comparison to the published sequences for the ion channel proteins.

Example 2 Insertion of Ion Channel cDNA into Delivery Vehicles

Preferably, ion channel cDNA is inserted into either plasmid or adenoviral vectors. Plasmid vectors include for example, pGEM3 or pBR322, as set forth in Acsadi, et al., The New Biol., 1991, 3, 71-81, and Gal, et al., Lab. Invest., 1993, 68, 18-25. Adenoviral vectors include for example, adenovirus serotype 5, Ad5, as set forth in French, et al., Circulation, 1994, 90, 2414-2424, and Johns, J. Clin. Invest., 1995, 96, 1152-1158.

Preferably, the primers used to amplify the ion channel nucleic acid molecules are designed with unique endonuclease restriction sites located at the 5′ terminus. In the absence of such design, polylinker arms, containing unique restriction sites, can be ligated thereto. After cutting the purified PCR products with the appropriate restriction endonuclease(s), the plasmid vector, comprising a polylinker, is also cut with the same restriction endonuclease(s), affording the ion channel nucleic acid molecule a site at which to ligate. In a similar manner, recombinant adenovirus (Gluzman, et al., in Eukaryotic Viral Vectors, Gluzman, ed., Cold Spring Harbor Press, 1982, pp. 187-192, French, et al., Circulation, 1994, 90, 2414-2424, and Johns, J. Clin. Invest., 1995, 96, 1152-1158) containing ion channel cDNA molecules are prepared in accordance with standard techniques well known to those skilled in the art.

It is contemplated that variations of the above-described invention may be constructed that are consistent with the spirit of the invention.

                   #             SEQUENCE LISTING (1) GENERAL INFORMATION:    (iii) NUMBER OF SEQUENCES: 12 (2) INFORMATION FOR SEQ ID NO: 1:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 6048 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: double           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #1: ATG GCA AAC TTC CTA TTA CCT CGG GGC ACC AG #C AGC TTC CGC AGG            #45 Met Ala Asn Phe Leu Leu Pro Arg Gly Thr Se #r Ser Phe Arg Arg  1                5  #                 10  #                 15 TTC ACA CGG GAG TCC CTG GCA GCC ATC GAG AA #G CGC ATG GCG GAG            #90 Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Ly #s Arg Met Ala Glu                  20  #                 25  #                 30 AAG CAA GCC CGC GGC TCA ACC ACC TTG CAG GA #G AGC CGA GAG GGG          13 #5 Lys Gln Ala Arg Gly Ser Thr Thr Leu Gln Gl #u Ser Arg Glu Gly                  35  #                 40  #                 45 CTG CCC GAG GAG GAG GCT CCC CGG CCC CAG CT #G GAC CTG CAG GCC          18 #0 Leu Pro Glu Glu Glu Ala Pro Arg Pro Gln Le #u Asp Leu Gln Ala                  50  #                 55  #                 60 TCC AAA AAG CTG CCA GAT CTC TAT GGC AAT CC #A CCC CAA GAG CTC          22 #5 Ser Lys Lys Leu Pro Asp Leu Tyr Gly Asn Pr #o Pro Gln Glu Leu                  65  #                 70  #                 75 ATC GGA GAG CCC CTG GAG GAC CTG GAC CCC TT #C TAT AGC ACC CAA          27 #0 Ile Gly Glu Pro Leu Glu Asp Leu Asp Pro Ph #e Tyr Ser Thr Gln                  80  #                 85  #                 90 AAG ACT TTC ATC GTA CTG AAT AAA GGC AAG AC #C ATC TTC CGG TTC          31 #5 Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Th #r Ile Phe Arg Phe                  95  #                100  #                105 AGT GCC ACC AAC GCC TTG TAT GTC CTC AGT CC #C TTC CAC CCA GTT          36 #0 Ser Ala Thr Asn Ala Leu Tyr Val Leu Ser Pr #o Phe His Pro Val                 110   #               115   #               120 CGG AGA GCG GCT GTG AAG ATT CTG GTT CAC TC #G CTC TTC AAC ATG          40 #5 Arg Arg Ala Ala Val Lys Ile Leu Val His Se #r Leu Phe Asn Met                 125   #               130   #               135 CTC ATC ATG TGC ACC ATC CTC ACC AAC TGC GT #G TTC ATG GCC CAG          45 #0 Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Va #l Phe Met Ala Gln                 140   #               145   #               150 CAC GAC CCT CCA CCC TGG ACC AAG TAT GTC GA #G TAC ACC TTC ACC          49 #5 His Asp Pro Pro Pro Trp Thr Lys Tyr Val Gl #u Tyr Thr Phe Thr                 155   #               160   #               165 GCC ATT TAC ACC TTT GAG TCT CTG GTC AAG AT #T CTG GCT CGA GCT          54 #0 Ala Ile Tyr Thr Phe Glu Ser Leu Val Lys Il #e Leu Ala Arg Ala                 170   #               175   #               180 TTC TGC CTG CAC GCG TTC ACT TTC CTT CGG GA #C CCA TGG AAC TGG          58 #5 Phe Cys Leu His Ala Phe Thr Phe Leu Arg As #p Pro Trp Asn Trp                 185   #               190   #               195 CTG GAC TTT AGT GTG ATT ATC ATG GCA TAC AC #A ACT GAA TTT GTG          63 #0 Leu Asp Phe Ser Val Ile Ile Met Ala Tyr Th #r Thr Glu Phe Val                 200   #               205   #               210 GAC CTG GGC AAT GTC TCA GCC TTA CGC ACC TT #C CGA GTC CTC CGG          67 #5 Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Ph #e Arg Val Leu Arg                 215   #               220   #               225 GCC CTG AAA ACT ATA TCA GTC ATT TCA GGG CT #G AAG ACC ATC GTG          72 #0 Ala Leu Lys Thr Ile Ser Val Ile Ser Gly Le #u Lys Thr Ile Val                 230   #               235   #               240 GGG GCC CTG ATC CAG TCT GTG AAG AAG CTG GC #T GAT GTG ATG GTC          76 #5 Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Al #a Asp Val Met Val                 245   #               250   #               255 CTC ACA GTC TTC TGC CTC AGC GTC TTT GCC CT #C ATC GGC CTG CAG          81 #0 Leu Thr Val Phe Cys Leu Ser Val Phe Ala Le #u Ile Gly Leu Gln                 260   #               265   #               270 CTC TTC ATG GGC AAC CTA AGG CAC AAG TGT GT #G CGC AAC TTC ACA          85 #5 Leu Phe Met Gly Asn Leu Arg His Lys Cys Va #l Arg Asn Phe Thr                 275   #               280   #               285 GCG CTC AAC GGC ACC AAC GGC TCC GTG GAG GC #C GAC GGC TTG GTC          90 #0 Ala Leu Asn Gly Thr Asn Gly Ser Val Glu Al #a Asp Gly Leu Val                 290   #               295   #               300 TGG GAA TCC CTG GAC CTT TAC CTC AGT GAT CC #A GAA AAT TAC CTG          94 #5 Trp Glu Ser Leu Asp Leu Tyr Leu Ser Asp Pr #o Glu Asn Tyr Leu                 305   #               310   #               315 CTC AAG AAC GGC ACC TCT GAT GTG TTA CTG TG #T GGG AAC AGC TCT          99 #0 Leu Lys Asn Gly Thr Ser Asp Val Leu Leu Cy #s Gly Asn Ser Ser                 320   #               325   #               330 GAC GCT GGG ACA TGT CCG GAG GGC TAC CGG TG #C CTA AAG GCA GGC         1035 Asp Ala Gly Thr Cys Pro Glu Gly Tyr Arg Cy #s Leu Lys Ala Gly                 335   #               340   #               345 GAG AAC CCC GAC CAC GGC TAC ACC AGC TTC GA #T TCC TTT GCC TGG         1080 Glu Asn Pro Asp His Gly Tyr Thr Ser Phe As #p Ser Phe Ala Trp                 350   #               355   #               360 GCC TTT CTT GCA CTC TTC CGC CTG ATG ACG CA #G GAC TGC TGG GAG         1125 Ala Phe Leu Ala Leu Phe Arg Leu Met Thr Gl #n Asp Cys Trp Glu                 365   #               370   #               375 CGC CTC TAT CAG CAG ACC CTC AGG TCC GCA GG #G AAG ATC TAC ATG         1170 Arg Leu Tyr Gln Gln Thr Leu Arg Ser Ala Gl #y Lys Ile Tyr Met                 380   #               385   #               390 ATC TTC TTC ATG CTT GTC ATC TTC CTG GGG TC #C TTC TAC CTG GTG         1215 Ile Phe Phe Met Leu Val Ile Phe Leu Gly Se #r Phe Tyr Leu Val                 395   #               400   #               405 AAC CTG ATC CTG GCC GTG GTC GCA ATG GCC TA #T GAG GAG CAA AAC         1260 Asn Leu Ile Leu Ala Val Val Ala Met Ala Ty #r Glu Glu Gln Asn                 410   #               415   #               420 CAA GCC ACC ATC GCT GAG ACC GAG GAG AAG GA #A AAG CGC TTC CAG         1305 Gln Ala Thr Ile Ala Glu Thr Glu Glu Lys Gl #u Lys Arg Phe Gln                 425   #               430   #               435 GAG GCC ATG GAA ATG CTC AAG AAA GAA CAC GA #G GCC CTC ACC ATC         1350 Glu Ala Met Glu Met Leu Lys Lys Glu His Gl #u Ala Leu Thr Ile                 440   #               445   #               450 AGG GGT GTG GAT ACC GTG TCC CGT AGC TCC TT #G GAG ATG TCC CCT         1395 Arg Gly Val Asp Thr Val Ser Arg Ser Ser Le #u Glu Met Ser Pro                 455   #               460   #               465 TTG GCC CCA GTA AAC AGC CAT GAG AGA AGA AG #C AAG AGG AGA AAA         1440 Leu Ala Pro Val Asn Ser His Glu Arg Arg Se #r Lys Arg Arg Lys                 470   #               475   #               480 CGG ATG TCT TCA GGA ACT GAG GAG TGT GGG GA #G GAC AGG CTC CCC         1485 Arg Met Ser Ser Gly Thr Glu Glu Cys Gly Gl #u Asp Arg Leu Pro                 485   #               490   #               495 AAG TCT GAC TCA GAA GAT GGT CCC AGA GCA AT #G AAT CAT CTC AGC         1530 Lys Ser Asp Ser Glu Asp Gly Pro Arg Ala Me #t Asn His Leu Ser                 500   #               505   #               510 CTC ACC CGT GGC CTC AGC AGG ACT TCT ATG AA #G CCA CGT TCC AGC         1575 Leu Thr Arg Gly Leu Ser Arg Thr Ser Met Ly #s Pro Arg Ser Ser                 515   #               520   #               525 CGC GGG AGC ATT TTC ACC TTT CGC AGG CGA GA #C CTG GGT TCT GAA         1620 Arg Gly Ser Ile Phe Thr Phe Arg Arg Arg As #p Leu Gly Ser Glu                 530   #               535   #               540 GCA GAT TTT GCA GAT GAT GAA AAC AGC ACA GC #G CGG GAG AGC GAG         1665 Ala Asp Phe Ala Asp Asp Glu Asn Ser Thr Al #a Arg Glu Ser Glu                 545   #               550   #               555 AGC CAC CAC ACA TCA CTG CTG GTG CCC TGG CC #C CTG CGC CGG ACC         1710 Ser His His Thr Ser Leu Leu Val Pro Trp Pr #o Leu Arg Arg Thr                 560   #               565   #               570 AGT GCC CAG GGA CAG CCC AGT CCC GGA ACC TC #G GCT CCT GGC CAC         1755 Ser Ala Gln Gly Gln Pro Ser Pro Gly Thr Se #r Ala Pro Gly His                 575   #               580   #               585 GCC CTC CAT GGC AAA AAG AAC AGC ACT GTG GA #C TGC AAT GGG GTG         1800 Ala Leu His Gly Lys Lys Asn Ser Thr Val As #p Cys Asn Gly Val                 590   #               595   #               600 GTC TCA TTA CTG GGG GCA GGC GAC CCA GAG GC #C ACA TCC CCA GGA         1845 Val Ser Leu Leu Gly Ala Gly Asp Pro Glu Al #a Thr Ser Pro Gly                 605   #               610   #               615 AGC CAC CTC CTC CGC CCT GTG ATG CTA GAG CA #C CCG CCA GAC ACG         1890 Ser His Leu Leu Arg Pro Val Met Leu Glu Hi #s Pro Pro Asp Thr                 620   #               625   #               630 ACC ACG CCA TCG GAG GAG CCA GGC GGC CCC CA #G ATG CTG ACC TCC         1935 Thr Thr Pro Ser Glu Glu Pro Gly Gly Pro Gl #n Met Leu Thr Ser                 635   #               640   #               645 CAG GCT CCG TGT GTA GAT GGC TTC GAG GAG CC #A GGA GCA CGG CAG         1980 Gln Ala Pro Cys Val Asp Gly Phe Glu Glu Pr #o Gly Ala Arg Gln                 650   #               655   #               660 CGG GCC CTC AGC GCA GTC AGC GTC CTC ACA AG #C GCA CTG GAA GAG         2025 Arg Ala Leu Ser Ala Val Ser Val Leu Thr Se #r Ala Leu Glu Glu                 665   #               670   #               675 TTA GAG GAG TCT CGC CAC AAG TGT CCA CCA TG #C TGG AAC CGT CTC         2070 Leu Glu Glu Ser Arg His Lys Cys Pro Pro Cy #s Trp Asn Arg Leu                 680   #               685   #               690 GCC CAG CGC TAC CTG ATC TGG GAG TGC TGC CC #G CTG TGG ATG TCC         2115 Ala Gln Arg Tyr Leu Ile Trp Glu Cys Cys Pr #o Leu Trp Met Ser                 695   #               700   #               705 ATC AAG CAG GGA GTG AAG TTG GTG GTC ATG GA #C CCG TTT ACT GAC         2160 Ile Lys Gln Gly Val Lys Leu Val Val Met As #p Pro Phe Thr Asp                 710   #               715   #               720 CTC ACC ATC ACT ATG TGC ATC GTA CTC AAC AC #A CTC TTC ATG GCG         2205 Leu Thr Ile Thr Met Cys Ile Val Leu Asn Th #r Leu Phe Met Ala                 725   #               730   #               735 CTG GAG CAC TAC AAC ATG ACA AGT GAA TTC GA #G GAG ATG CTG CAG         2250 Leu Glu His Tyr Asn Met Thr Ser Glu Phe Gl #u Glu Met Leu Gln                 740   #               745   #               750 GTC GGA AAC CTG GTC TTC ACA GGG ATT TTC AC #A GCA GAG ATG ACC         2295 Val Gly Asn Leu Val Phe Thr Gly Ile Phe Th #r Ala Glu Met Thr                 755   #               760   #               765 TTC AAG ATC ATT GCC CTC GAC CCC TAC TAC TA #C TTC CAA CAG GGC         2340 Phe Lys Ile Ile Ala Leu Asp Pro Tyr Tyr Ty #r Phe Gln Gln Gly                 770   #               775   #               780 TGG AAC ATC TTC GAC AGC ATC ATC GTC ATC CT #T AGC CTC ATG GAG         2385 Trp Asn Ile Phe Asp Ser Ile Ile Val Ile Le #u Ser Leu Met Glu                 785   #               790   #               795 CTG GGC CTG TCC CGC ATG AGC AAC TTG TCG GT #G CTG CGC TCC TTC         2430 Leu Gly Leu Ser Arg Met Ser Asn Leu Ser Va #l Leu Arg Ser Phe                 800   #               805   #               810 CGC CTG CTG CGG GTC TTC AAG CTG GCC AAA TC #A TGG CCC ACC CTG         2475 Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Se #r Trp Pro Thr Leu                 815   #               820   #               825 AAC ACA CTC ATC AAG ATC ATC GGG AAC TCA GT #G GGG GCA CTG GGG         2520 Asn Thr Leu Ile Lys Ile Ile Gly Asn Ser Va #l Gly Ala Leu Gly                 830   #               835   #               840 AAC CTG ACA CTG GTG CTA GCC ATC ATC GTG TT #C ATC TTT GCT GTG         2565 Asn Leu Thr Leu Val Leu Ala Ile Ile Val Ph #e Ile Phe Ala Val                 845   #               850   #               855 GTG GGC ATG CAG CTC TTT GGC AAG AAC TAC TC #G GAG CTG AGG GAC         2610 Val Gly Met Gln Leu Phe Gly Lys Asn Tyr Se #r Glu Leu Arg Asp                 860   #               865   #               870 AGC GAC TCA GGC CTG CTG CCT CGC TGG CAC AT #G ATG GAC TTC TTT         2655 Ser Asp Ser Gly Leu Leu Pro Arg Trp His Me #t Met Asp Phe Phe                 875   #               880   #               885 CAT GCC TTC CTA ATC ATC TTC CGC ATC CTC TG #T GGA GAG TGG ATC         2700 His Ala Phe Leu Ile Ile Phe Arg Ile Leu Cy #s Gly Glu Trp Ile                 890   #               895   #               900 GAG ACC ATG TGG GAC TGC ATG GAG GTG TCG GG #G CAG TCA TTA TGC         2745 Glu Thr Met Trp Asp Cys Met Glu Val Ser Gl #y Gln Ser Leu Cys                 905   #               910   #               915 CTG CTG GTC TTC TTG CTT GTT ATG GTC ATT GG #C AAC CTT GTG GTC         2790 Leu Leu Val Phe Leu Leu Val Met Val Ile Gl #y Asn Leu Val Val                 920   #               925   #               930 CTG AAT CTC TTC CTG GCC TTG CTG CTC AGC TC #C TTC AGT GCA GAC         2835 Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Se #r Phe Ser Ala Asp                 935   #               940   #               945 AAC CTC ACA GCC CCT GAT GAG GAC AGA GAG AT #G AAC AAC CTC CAG         2880 Asn Leu Thr Ala Pro Asp Glu Asp Arg Glu Me #t Asn Asn Leu Gln                 950   #               955   #               960 CTG GCC CTG GCC CGC ATC CAG AGG GGC CTG CG #C TTT GTC AAG CGG         2925 Leu Ala Leu Ala Arg Ile Gln Arg Gly Leu Ar #g Phe Val Lys Arg                 965   #               970   #               975 ACC ACC TGG GAT TTC TGC TGT GGT CTC CTG CG #G CAC CGG CCT CAG         2970 Thr Thr Trp Asp Phe Cys Cys Gly Leu Leu Ar #g His Arg Pro Gln                 980   #               985   #               990 AAG CCC GCA GCC CTT GCC GCC CAG GGC CAG CT #G CCC AGC TGC ATT         3015 Lys Pro Ala Ala Leu Ala Ala Gln Gly Gln Le #u Pro Ser Cys Ile                 995   #               1000   #              1005 GCC ACC CCC TAC TCC CCG CCA CCC CCA GAG AC #G GAG AAG GTG CCT         3060 Ala Thr Pro Tyr Ser Pro Pro Pro Pro Glu Th #r Glu Lys Val Pro                 1010  #               1015   #              1020 CCC ACC CGC AAG GAA ACA CAG TTT GAG GAA GG #C GAG CAA CCA GGC         3105 Pro Thr Arg Lys Glu Thr Gln Phe Glu Glu Gl #y Glu Gln Pro Gly                 1025  #               1030   #              1035 CAG GGC ACC CCC GGG GAT CCA GAC GCC GTG TG #T GTG CCC ATC GCT         3150 Gln Gly Thr Pro Gly Asp Pro Glu Pro Val Cy #s Val Pro Ile Ala                 1040  #               1045   #              1050 GTG GCC GAG TCA GAC ACA GAT GAC CAA GAA GA #G GAT GAG GAG AAC         3195 Val Ala Glu Ser Asp Thr Asp Asp Gln Glu Gl #u Asp Glu Glu Asn                 1055  #               1060   #              1065 AGC CTG GGC ACG GAG GAG GAG TCC AGC AAG CA #G CAG GAA TCC CAG         3240 Ser Leu Gly Thr Glu Glu Glu Ser Ser Lys Gl #n Gln Glu Ser Gln                 1070  #               1075   #              1080 CCT GTG TCC GGC TGG CCC AGA GGC CCT CCG GA #T TCC AGG ACC TGG         3285 Pro Val Ser Gly Trp Pro Arg Gly Pro Pro As #p Ser Arg Thr Trp                 1085  #               1090   #              1095 AGC CAG GTG TCA GCG ACT GCC TCC TCT GAG GC #C GAG GCC AGT GCA         3330 Ser Gln Val Ser Ala Thr Ala Ser Ser Glu Al #a Glu Ala Ser Ala                 1100  #               1105   #              1110 TCT CAG GCC GAC TGG CGG CAG CAG TGG AAA GC #G GAA CCC CAG GCC         3375 Ser Gln Ala Asp Trp Arg Gln Gln Trp Lys Al #a Glu Pro Gln Ala                 1115  #               1120   #              1125 CCA GGG TGC GGT GAG ACC CCA GAG GAC AGT TG #C TCC GAG GGC AGC         3420 Pro Gly Cys Gly Glu Thr Pro Glu Asp Ser Cy #s Ser Glu Gly Ser                 1130  #               1135   #              1140 ACA GCA GAC ATG ACC AAC ACC GCT GAG CTC CT #G GAG CAG ATC CCT         3465 Thr Ala Asp Met Thr Asn Thr Ala Glu Leu Le #u Glu Gln Ile Pro                 1145  #               1150   #              1155 GAC CTC GGC CAG GAT GTC AAG GAC CCA GAG GA #C TGC TTC ACT GAA         3510 Asp Leu Gly Gln Asp Val Lys Asp Pro Glu As #p Cys Phe Thr Glu                 1160  #               1165   #              1170 GGC TGT GTC CGG CGC TGT CCC TGC TGT GCG GT #G GAC ACC ACA CAG         3555 Gly Cys Val Arg Arg Cys Pro Cys Cys Ala Va #l Asp Thr Thr Gln                 1175  #               1180   #              1185 GCC CCA GGG AAG GTC TGG TGG CGG TTG CGC AA #G ACC TGC TAC CAC         3600 Ala Pro Gly Lys Val Trp Trp Arg Leu Arg Ly #s Thr Cys Tyr His                 1190  #               1195   #              1200 ATC GTG GAG CAC AGC TGG TTC GAG ACA TTC AT #C ATC TTC ATG ATC         3645 Ile Val Glu His Ser Trp Phe Glu Thr Phe Il #e Ile Phe Met Ile                 1205  #               1210   #              1215 CTA CTC AGC AGT GGA GCG CTG GCC TTC GAG GA #C ATC TAC CTA GAG         3690 Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu As #p Ile Tyr Leu Glu                 1220  #               1225   #              1230 GAG CGG AAG ACC ATC AAG GTT CTG CTT GAG TA #T GCC GAC AAG ATG         3735 Glu Arg Lys Thr Ile Lys Val Leu Leu Glu Ty #r Ala Asp Lys Met                 1235  #               1240   #              1245 TTC ACA TAT GTC TTC GTG CTG GAG ATG CTG CT #C AAG TGG GTG GCC         3780 Phe Thr Tyr Val Phe Val Leu Glu Met Leu Le #u Lys Trp Val Ala                 1250  #               1255   #              1260 TAC GGC TTC AAG AAG TAC TTC ACC AAT GCC TG #G TGC TGG CTC GAC         3825 Tyr Gly Phe Lys Lys Tyr Phe Thr Asn Ala Tr #p Cys Trp Leu Asp                 1265  #               1270   #              1275 TTC CTC ATC GTA GAC GTC TCT CTG GTC AGC CT #G GTG GCC AAC ACC         3870 Phe Leu Ile Val Asp Val Ser Leu Val Ser Le #u Val Ala Asn Thr                 1280  #               1285   #              1290 CTG GGC TTT GCC GAG ATG GGC CCC ATC AAG TC #A CTG CGG ACG CTG         3915 Leu Gly Phe Ala Glu Met Gly Pro Ile Lys Se #r Leu Arg Thr Leu                 1295  #               1300   #              1305 CGT GCA CTC CGT CCT CTG AGA GCT CTG TCA CG #A TTT GAG GGC ATG         3960 Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Ar #g Phe Glu Gly Met                 1310  #               1315   #              1320 AGG GTG GTG GTC AAT GCC CTG GTG GGC GCC AT #C CCG TCC ATC ATG         4005 Arg Val Val Val Asn Ala Leu Val Gly Ala Il #e Pro Ser Ile Met                 1325  #               1330   #              1335 AAC GTC CTC CTC GTC TGC CTC ATC TTC TGG CT #C ATC TTC AGC ATC         4050 Asn Val Leu Leu Val Cys Leu Ile Phe Trp Le #u Ile Phe Ser Ile                 1340  #               1345   #              1350 ATG GGC GTG AAC CTC TTT GCG GGG AAG TTT GG #G AGG TGC ATC AAC         4095 Met Gly Val Asn Leu Phe Ala Gly Lys Phe Gl #y Arg Cys Ile Asn                 1355  #               1360   #              1365 CAG ACA GAG GGA GAC TTG CCT TTG AAC TAC AC #C ATC GTG AAC AAC         4140 Gln Thr Glu Gly Asp Leu Pro Leu Asn Tyr Th #r Ile Val Asn Asn                 1370  #               1375   #              1380 AAG AGC CAG TGT GAG TCC TTG AAC TTG ACC GG #A GAA TTG TAC TGG         4185 Lys Ser Gln Cys Glu Ser Leu Asn Leu Thr Gl #y Glu Leu Tyr Trp                 1385  #               1390   #              1395 ACC AAG GTG AAA GTC AAC TTT GAC AAC GTG GG #G GCC GGG TAC CTG         4230 Thr Lys Val Lys Val Asn Phe Asp Asn Val Gl #y Ala Gly Tyr Leu                 1400  #               1405   #              1410 GCC CTT CTG CAG GTG GCA ACA TTT AAA GGC TG #G ATG GAC ATT ATG         4275 Ala Leu Leu Gln Val Ala Thr Phe Lys Gly Tr #p Met Asp Ile Met                 1415  #               1420   #              1425 TAT GCA GCT GTG GAC TCC AGG GGG TAT GAA GA #G CAG CCT CAG TGG         4320 Tyr Ala Ala Val Asp Ser Arg Gly Tyr Glu Gl #u Gln Pro Gln Trp                 1430  #               1435   #              1440 GAA TAC AAC CTC TAC ATG TAC ATC TAT TTT GT #C ATT TTC ATC ATC         4365 Glu Tyr Asn Leu Tyr Met Tyr Ile Tyr Phe Va #l Ile Phe Ile Ile                 1445  #               1450   #              1455 TTT GGG TCT TTC TTC ACC CTG AAC CTC TTT AT #T GGT GTC ATC ATT         4410 Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Il #e Gly Val Ile Ile                 1460  #               1465   #              1470 GAC AAC TTC AAC CAA CAG AAG AAA AAG TTA GG #G GGC CAG GAC ATC         4455 Asp Asn Phe Asn Gln Gln Lys Lys Lys Leu Gl #y Gly Gln Asp Ile                 1475  #               1480   #              1485 TTC ATG ACA GAG GAG CAG AAG AAG TAC TAC AA #T GCC ATG AAG AAG         4500 Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr As #n Ala Met Lys Lys                 1490  #               1495   #              1500 CTG GGC TCC AAG AAG CCC CAG AAG CCC ATC CC #A CGG CCC CTG AAC         4545 Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pr #o Arg Pro Leu Asn                 1505  #               1510   #              1515 AAG TAC CAG GGC TTC ATA TTC GAC ATT GTG AC #C AAG CAG GCC TTT         4590 Lys Tyr Gln Gly Phe Ile Phe Asp Ile Val Th #r Lys Gln Ala Phe                 1520  #               1525   #              1530 GAC GTC ACC ATC ATG TTT CTG ATC TGC TTG AA #T ATG GTG ACC ATG         4635 Asp Val Thr Ile Met Phe Leu Ile Cys Leu As #n Met Val Thr Met                 1535  #               1540   #              1545 ATG GTG GAG ACA GAT GAC CAA AGT CCT GAG AA #A ATC AAC ATC TTG         4680 Met Val Glu Thr Asp Asp Gln Ser Pro Glu Ly #s Ile Asn Ile Leu                 1550  #               1555   #              1560 GCC AAG ATC AAC CTG CTC TTT GTG GCC ATC TT #C ACA GGC GAG TGT         4725 Ala Lys Ile Asn Leu Leu Phe Val Ala Ile Ph #e Thr Gly Glu Cys                 1565  #               1570   #              1575 ATT GTC AAG CTG GCT GCC CTG CGC CAC TAC TA #C TTC ACC AAC AGC         4770 Ile Val Lys Leu Ala Ala Leu Arg His Tyr Ty #r Phe Thr Asn Ser                 1580  #               1585   #              1590 TGG AAT ATC TTC GAC TTC GTG GTT GTC ATC CT #C TCC ATC GTG GGC         4815 Trp Asn Ile Phe Asp Phe Val Val Val Ile Le #u Ser Ile Val Gly                 1595  #               1600   #              1605 ACT GTG CTC TCG GAC ATC ATC CAG AAG TAC TT #C TTC TCC CCG ACG         4860 Thr Val Leu Ser Asp Ile Ile Gln Lys Tyr Ph #e Phe Ser Pro Thr                 1610  #               1615   #              1620 CTC TTC CGA GTC ATC CGC CTG GCC CGA ATA GG #C CGC ATC CTC AGA         4905 Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gl #y Arg Ile Leu Arg                 1625  #               1630   #              1635 CTG ATC CGA GGG GCC AAG GGG ATC CGC ACG CT #G CTC TTT GCC CTC         4950 Leu Ile Arg Gly Ala Lys Gly Ile Arg Thr Le #u Leu Phe Ala Leu                 1640  #               1645   #              1650 ATG ATG TCC CTG CCT GCC CTC TTC AAC ATC GG #G CTG CTG CTC TTC         4995 Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gl #y Leu Leu Leu Phe                 1655  #               1660   #              1665 CTC GTC ATG TTC ATC TAC TCC ATC TTT GGC AT #G GCC AAC TTC GCT         5040 Leu Val Met Phe Ile Tyr Ser Ile Phe Gly Me #t Ala Asn Phe Ala                 1670  #               1675   #              1680 TAT GTC AAG TGG GAG GCT GGC ATC GAC GAC AT #G TTC AAC TTC CAG         5085 Tyr Val Lys Trp Glu Ala Gly Ile Asp Asp Me #t Phe Asn Phe Gln                 1685  #               1690   #              1695 ACC TTC GCC AAC AGC ATG CTG TGC CTC TTC CA #G ATC ACC ACG TCG         5130 Thr Phe Ala Asn Ser Met Leu Cys Leu Phe Gl #n Ile Thr Thr Ser                 1700  #               1705   #              1710 GCC GGC TGG GAT GGC CTC CTC AGC CCC ATC CT #C AAC ACT GGG CCG         5175 Ala Gly Trp Asp Gly Leu Leu Ser Pro Ile Le #u Asn Thr Gly Pro                 1715  #               1720   #              1725 CCC TAC TGC GAC CCC ACT CTG CCC AAC AGC AA #T GGC TCT CGG GGG         5220 Pro Tyr Cys Asp Pro Thr Leu Pro Asn Ser As #n Gly Ser Arg Gly                 1730  #               1735   #              1740 GAC TGC GGG AGC CCA GCC GTG GGC ATC CTC TT #C TTC ACC ACC TAC         5265 Asp Cys Gly Ser Pro Ala Val Gly Ile Leu Ph #e Phe Thr Thr Tyr                 1745  #               1750   #              1755 ATC ATC ATC TCC TTC CTC ATC GTG GTC AAC AT #G TAC ATT GCC ATC         5310 Ile Ile Ile Ser Phe Leu Ile Val Val Asn Me #t Tyr Ile Ala Ile                 1760  #               1765   #              1770 ATC CTG GAG AAC TTC AGC GTG GCC ACG GAG GA #G AGC ACC GAG CCC         5355 Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Gl #u Ser Thr Glu Pro                 1775  #               1780   #              1785 CTG AGT GAG GAC GAC TTC GAT ATG TTC TAT GA #G ATC TGG GAG AAA         5400 Leu Ser Glu Asp Asp Phe Asp Met Phe Tyr Gl #u Ile Trp Glu Lys                 1790  #               1795   #              1800 TTT GAC CCA GAG GCC ACT CAG TTT ATT GAG TA #T TCG GTC CTG TCT         5445 Phe Asp Pro Glu Ala Thr Gln Phe Ile Glu Ty #r Ser Val Leu Ser                 1805  #               1810   #              1815 GAC TTT GCC GAC GCC CTG TCT GAG CCA CTC CG #T ATC GCC AAG CCC         5490 Asp Phe Ala Asp Ala Leu Ser Glu Pro Leu Il #e Arg Ala Lys Pro                 1820  #               1825   #              1830 AAC CAG ATA AGC CTC ATC AAC ATG GAC CTG CC #C ATG GTG AGT GGG         5535 Asn Gln Ile Ser Leu Ile Asn Met Asp Leu Pr #o Met Val Ser Gly                 1835  #               1840   #              1845 GAC CGC ATC CAT TGC ATG GAC ATT CTC TTT GC #C TTC ACC AAA AGG         5580 Asp Arg Ile His Cys Met Asp Ile Leu Phe Al #a Phe Thr Lys Arg                 1850  #               1855   #              1860 GTC CTG GGG GAG TCT GGG GAG ATG GAC GCC CT #G AAG ATC CAG ATG         5625 Val Leu Gly Glu Ser Gly Glu Met Asp Ala Le #u Lys Ile Gln Met                 1865  #               1870   #              1875 GAG GAG AAG TTC ATG GCA GCC AAC CCA TCC AA #G ATC TCC TAC GAG         5670 Glu Glu Lys Phe Met Ala Ala Asn Pro Ser Ly #s Ile Ser Tyr Glu                 1880  #               1885   #              1890 CCC ATC ACC ACC ACA CTC CGG CGC AAG CAC GA #A GAG GTG TCG GCC         5715 Pro Ile Thr Thr Thr Leu Arg Arg Lys His Gl #u Glu Val Ser Ala                 1895  #               1900   #              1905 ATG GTT ATC CAG AGA GCC TTC CGC AGG CAC CT #G CTG CAA CGC TCT         5760 Met Val Ile Gln Arg Ala Phe Arg Arg His Le #u Leu Gln Arg Ser                 1910  #               1915   #              1920 TTG AAG CAT GCC TCC TTC CTC TTC CGT CAG CA #G GCG GGC AGC GGC         5805 Leu Lys His Ala Ser Phe Leu Phe Arg Gln Gl #n Ala Gly Ser Gly                 1925  #               1930   #              1935 CTC TCC GAA GAG GAT GCC CCT GAG CGA GAG GG #C CTC ATC GCC TAC         5850 Leu Ser Glu Glu Asp Ala Pro Glu Arg Glu Gl #y Leu Ile Ala Tyr                 1940  #               1945   #              1950 GTG ATG AGT GAG AAC TTC TCC CGA CCC CTT GG #C CCA CCC TCC AGC         5895 Val Met Ser Glu Asn Phe Ser Arg Pro Leu Gl #y Pro Pro Ser Ser                 1955  #               1960   #              1965 TCC TCC ATC TCC TCC ACT TCC TTC CCA CCC TC #C TAT GAC AGT GTC         5940 Ser Ser Ile Ser Ser Thr Ser Phe Pro Pro Se #r Tyr Asp Ser Val                 1970  #               1975   #              1980 ACT AGA GCC ACC AGC GAT AAC CTC CAG GTG CG #G GGG TCT GAC TAC         5985 Thr Arg Ala Thr Ser Asp Asn Leu Gln Val Ar #g Gly Ser Asp Tyr                 1985  #               1990   #              1995 AGC CAC AGT GAA GAT CTC GCC GAC TTC CCC CC #T TCT CCG GAC AGG         6030 Ser His Ser Glu Asp Leu Ala Asp Phe Pro Pr #o Ser Pro Asp Arg                 2000  #               2005   #              2010 GAC CGT GAG TCC ATC GTG          #                   #                   #6048 Asp Arg Glu Ser Ile Val                 2015 (2) INFORMATION FOR SEQ ID NO: 2:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 2016 amino  #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: unknown     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #2: Met Ala Asn Phe Leu Leu Pro Arg Gly Thr Se #r Ser Phe Arg Arg  1                5  #                 10  #                 15 Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Ly #s Arg Met Ala Glu                  20  #                 25  #                 30 Lys Gln Ala Arg Gly Ser Thr Thr Leu Gln Gl #u Ser Arg Glu Gly                  35  #                 40  #                 45 Leu Pro Glu Glu Glu Ala Pro Arg Pro Gln Le #u Asp Leu Gln Ala                  50  #                 55  #                 60 Ser Lys Lys Leu Pro Asp Leu Tyr Gly Asn Pr #o Pro Gln Glu Leu                  65  #                 70  #                 75 Ile Gly Glu Pro Leu Glu Asp Leu Asp Pro Ph #e Tyr Ser Thr Gln                  80  #                 85  #                 90 Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Th #r Ile Phe Arg Phe                  95  #                100  #                105 Ser Ala Thr Asn Ala Leu Tyr Val Leu Ser Pr #o Phe His Pro Val                 110   #               115   #               120 Arg Arg Ala Ala Val Lys Ile Leu Val His Se #r Leu Phe Asn Met                 125   #               130   #               135 Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Va #l Phe Met Ala Gln                 140   #               145   #               150 His Asp Pro Pro Pro Trp Thr Lys Tyr Val Gl #u Tyr Thr Phe Thr                 155   #               160   #               165 Ala Ile Tyr Thr Phe Glu Ser Leu Val Lys Il #e Leu Ala Arg Ala                 170   #               175   #               180 Phe Cys Leu His Ala Phe Thr Phe Leu Arg As #p Pro Trp Asn Trp                 185   #               190   #               195 Leu Asp Phe Ser Val Ile Ile Met Ala Tyr Th #r Thr Glu Phe Val                 200   #               205   #               210 Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Ph #e Arg Val Leu Arg                 215   #               220   #               225 Ala Leu Lys Thr Ile Ser Val Ile Ser Gly Le #u Lys Thr Ile Val                 230   #               235   #               240 Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Al #a Asp Val Met Val                 245   #               250   #               255 Leu Thr Val Phe Cys Leu Ser Val Phe Ala Le #u Ile Gly Leu Gln                 260   #               265   #               270 Leu Phe Met Gly Asn Leu Arg His Lys Cys Va #l Arg Asn Phe Thr                 275   #               280   #               285 Ala Leu Asn Gly Thr Asn Gly Ser Val Glu Al #a Asp Gly Leu Val                 290   #               295   #               300 Trp Glu Ser Leu Asp Leu Tyr Leu Ser Asp Pr #o Glu Asn Tyr Leu                 305   #               310   #               315 Leu Lys Asn Gly Thr Ser Asp Val Leu Leu Cy #s Gly Asn Ser Ser                 320   #               325   #               330 Asp Ala Gly Thr Cys Pro Glu Gly Tyr Arg Cy #s Leu Lys Ala Gly                 335   #               340   #               345 Glu Asn Pro Asp His Gly Tyr Thr Ser Phe As #p Ser Phe Ala Trp                 350   #               355   #               360 Ala Phe Leu Ala Leu Phe Arg Leu Met Thr Gl #n Asp Cys Trp Glu                 365   #               370   #               375 Arg Leu Tyr Gln Gln Thr Leu Arg Ser Ala Gl #y Lys Ile Tyr Met                 380   #               385   #               390 Ile Phe Phe Met Leu Val Ile Phe Leu Gly Se #r Phe Tyr Leu Val                 395   #               400   #               405 Asn Leu Ile Leu Ala Val Val Ala Met Ala Ty #r Glu Glu Gln Asn                 410   #               415   #               420 Gln Ala Thr Ile Ala Glu Thr Glu Glu Lys Gl #u Lys Arg Phe Gln                 425   #               430   #               435 Glu Ala Met Glu Met Leu Lys Lys Glu His Gl #u Ala Leu Thr Ile                 440   #               445   #               450 Arg Gly Val Asp Thr Val Ser Arg Ser Ser Le #u Glu Met Ser Pro                 455   #               460   #               465 Leu Ala Pro Val Asn Ser His Glu Arg Arg Se #r Lys Arg Arg Lys                 470   #               475   #               480 Arg Met Ser Ser Gly Thr Glu Glu Cys Gly Gl #u Asp Arg Leu Pro                 485   #               490   #               495 Lys Ser Asp Ser Glu Asp Gly Pro Arg Ala Me #t Asn His Leu Ser                 500   #               505   #               510 Leu Thr Arg Gly Leu Ser Arg Thr Ser Met Ly #s Pro Arg Ser Ser                 515   #               520   #               525 Arg Gly Ser Ile Phe Thr Phe Arg Arg Arg As #p Leu Gly Ser Glu                 530   #               535   #               540 Ala Asp Phe Ala Asp Asp Glu Asn Ser Thr Al #a Arg Glu Ser Glu                 545   #               550   #               555 Ser His His Thr Ser Leu Leu Val Pro Trp Pr #o Leu Arg Arg Thr                 560   #               565   #               570 Ser Ala Gln Gly Gln Pro Ser Pro Gly Thr Se #r Ala Pro Gly His                 575   #               580   #               585 Ala Leu His Gly Lys Lys Asn Ser Thr Val As #p Cys Asn Gly Val                 590   #               595   #               600 Val Ser Leu Leu Gly Ala Gly Asp Pro Glu Al #a Thr Ser Pro Gly                 605   #               610   #               615 Ser His Leu Leu Arg Pro Val Met Leu Glu Hi #s Pro Pro Asp Thr                 620   #               625   #               630 Thr Thr Pro Ser Glu Glu Pro Gly Gly Pro Gl #n Met Leu Thr Ser                 635   #               640   #               645 Gln Ala Pro Cys Val Asp Gly Phe Glu Glu Pr #o Gly Ala Arg Gln                 650   #               655   #               660 Arg Ala Leu Ser Ala Val Ser Val Leu Thr Se #r Ala Leu Glu Glu                 665   #               670   #               675 Leu Glu Glu Ser Arg His Lys Cys Pro Pro Cy #s Trp Asn Arg Leu                 680   #               685   #               690 Ala Gln Arg Tyr Leu Ile Trp Glu Cys Cys Pr #o Leu Trp Met Ser                 695   #               700   #               705 Ile Lys Gln Gly Val Lys Leu Val Val Met As #p Pro Phe Thr Asp                 710   #               715   #               720 Leu Thr Ile Thr Met Cys Ile Val Leu Asn Th #r Leu Phe Met Ala                 725   #               730   #               735 Leu Glu His Tyr Asn Met Thr Ser Glu Phe Gl #u Glu Met Leu Gln                 740   #               745   #               750 Val Gly Asn Leu Val Phe Thr Gly Ile Phe Th #r Ala Glu Met Thr                 755   #               760   #               765 Phe Lys Ile Ile Ala Leu Asp Pro Tyr Tyr Ty #r Phe Gln Gln Gly                 770   #               775   #               780 Trp Asn Ile Phe Asp Ser Ile Ile Val Ile Le #u Ser Leu Met Glu                 785   #               790   #               795 Leu Gly Leu Ser Arg Met Ser Asn Leu Ser Va #l Leu Arg Ser Phe                 800   #               805   #               810 Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Se #r Trp Pro Thr Leu                 815   #               820   #               825 Asn Thr Leu Ile Lys Ile Ile Gly Asn Ser Va #l Gly Ala Leu Gly                 830   #               835   #               840 Asn Leu Thr Leu Val Leu Ala Ile Ile Val Ph #e Ile Phe Ala Val                 845   #               850   #               855 Val Gly Met Gln Leu Phe Gly Lys Asn Tyr Se #r Glu Leu Arg Asp                 860   #               865   #               870 Ser Asp Ser Gly Leu Leu Pro Arg Trp His Me #t Met Asp Phe Phe                 875   #               880   #               885 His Ala Phe Leu Ile Ile Phe Arg Ile Leu Cy #s Gly Glu Trp Ile                 890   #               895   #               900 Glu Thr Met Trp Asp Cys Met Glu Val Ser Gl #y Gln Ser Leu Cys                 905   #               910   #               915 Leu Leu Val Phe Leu Leu Val Met Val Ile Gl #y Asn Leu Val Val                 920   #               925   #               930 Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Se #r Phe Ser Ala Asp                 935   #               940   #               945 Asn Leu Thr Ala Pro Asp Glu Asp Arg Glu Me #t Asn Asn Leu Gln                 950   #               955   #               960 Leu Ala Leu Ala Arg Ile Gln Arg Gly Leu Ar #g Phe Val Lys Arg                 965   #               970   #               975 Thr Thr Trp Asp Phe Cys Cys Gly Leu Leu Ar #g His Arg Pro Gln                 980   #               985   #               990 Lys Pro Ala Ala Leu Ala Ala Gln Gly Gln Le #u Pro Ser Cys Ile                 995   #               1000   #              1005 Ala Thr Pro Tyr Ser Pro Pro Pro Pro Glu Th #r Glu Lys Val Pro                 1010  #               1015   #              1020 Pro Thr Arg Lys Glu Thr Gln Phe Glu Glu Gl #y Glu Gln Pro Gly                 1025  #               1030   #              1035 Gln Gly Thr Pro Gly Asp Pro Glu Pro Val Cy #s Val Pro Ile Ala                 1040  #               1045   #              1050 Val Ala Glu Ser Asp Thr Asp Asp Gln Glu Gl #u Asp Glu Glu Asn                 1055  #               1060   #              1065 Ser Leu Gly Thr Glu Glu Glu Ser Ser Lys Gl #n Gln Glu Ser Gln                 1070  #               1075   #              1080 Pro Val Ser Gly Trp Pro Arg Gly Pro Pro As #p Ser Arg Thr Trp                 1085  #               1090   #              1095 Ser Gln Val Ser Ala Thr Ala Ser Ser Glu Al #a Glu Ala Ser Ala                 1100  #               1105   #              1110 Ser Gln Ala Asp Trp Arg Gln Gln Trp Lys Al #a Glu Pro Gln Ala                 1115  #               1120   #              1125 Pro Gly Cys Gly Glu Thr Pro Glu Asp Ser Cy #s Ser Glu Gly Ser                 1130  #               1135   #              1140 Thr Ala Asp Met Thr Asn Thr Ala Glu Leu Le #u Glu Gln Ile Pro                 1145  #               1150   #              1155 Asp Leu Gly Gln Asp Val Lys Asp Pro Glu As #p Cys Phe Thr Glu                 1160  #               1165   #              1170 Gly Cys Val Arg Arg Cys Pro Cys Cys Ala Va #l Asp Thr Thr Gln                 1175  #               1180   #              1185 Ala Pro Gly Lys Val Trp Trp Arg Leu Arg Ly #s Thr Cys Tyr His                 1190  #               1195   #              1200 Ile Val Glu His Ser Trp Phe Glu Thr Phe Il #e Ile Phe Met Ile                 1205  #               1210   #              1215 Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu As #p Ile Tyr Leu Glu                 1220  #               1225   #              1230 Glu Arg Lys Thr Ile Lys Val Leu Leu Glu Ty #r Ala Asp Lys Met                 1235  #               1240   #              1245 Phe Thr Tyr Val Phe Val Leu Glu Met Leu Le #u Lys Trp Val Ala                 1250  #               1255   #              1260 Tyr Gly Phe Lys Lys Tyr Phe Thr Asn Ala Tr #p Cys Trp Leu Asp                 1265  #               1270   #              1275 Phe Leu Ile Val Asp Val Ser Leu Val Ser Le #u Val Ala Asn Thr                 1280  #               1285   #              1290 Leu Gly Phe Ala Glu Met Gly Pro Ile Lys Se #r Leu Arg Thr Leu                 1295  #               1300   #              1305 Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Ar #g Phe Glu Gly Met                 1310  #               1315   #              1320 Arg Val Val Val Asn Ala Leu Val Gly Ala Il #e Pro Ser Ile Met                 1325  #               1330   #              1335 Asn Val Leu Leu Val Cys Leu Ile Phe Trp Le #u Ile Phe Ser Ile                 1340  #               1345   #              1350 Met Gly Val Asn Leu Phe Ala Gly Lys Phe Gl #y Arg Cys Ile Asn                 1355  #               1360   #              1365 Gln Thr Glu Gly Asp Leu Pro Leu Asn Tyr Th #r Ile Val Asn Asn                 1370  #               1375   #              1380 Lys Ser Gln Cys Glu Ser Leu Asn Leu Thr Gl #y Glu Leu Tyr Trp                 1385  #               1390   #              1395 Thr Lys Val Lys Val Asn Phe Asp Asn Val Gl #y Ala Gly Tyr Leu                 1400  #               1405   #              1410 Ala Leu Leu Gln Val Ala Thr Phe Lys Gly Tr #p Met Asp Ile Met                 1415  #               1420   #              1425 Tyr Ala Ala Val Asp Ser Arg Gly Tyr Glu Gl #u Gln Pro Gln Trp                 1430  #               1435   #              1440 Glu Tyr Asn Leu Tyr Met Tyr Ile Tyr Phe Va #l Ile Phe Ile Ile                 1445  #               1450   #              1455 Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Il #e Gly Val Ile Ile                 1460  #               1465   #              1470 Asp Asn Phe Asn Gln Gln Lys Lys Lys Leu Gl #y Gly Gln Asp Ile                 1475  #               1480   #              1485 Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr As #n Ala Met Lys Lys                 1490  #               1495   #              1500 Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pr #o Arg Pro Leu Asn                 1505  #               1510   #              1515 Lys Tyr Gln Gly Phe Ile Phe Asp Ile Val Th #r Lys Gln Ala Phe                 1520  #               1525   #              1530 Asp Val Thr Ile Met Phe Leu Ile Cys Leu As #n Met Val Thr Met                 1535  #               1540   #              1545 Met Val Glu Thr Asp Asp Gln Ser Pro Glu Ly #s Ile Asn Ile Leu                 1550  #               1555   #              1560 Ala Lys Ile Asn Leu Leu Phe Val Ala Ile Ph #e Thr Gly Glu Cys                 1565  #               1570   #              1575 Ile Val Lys Leu Ala Ala Leu Arg His Tyr Ty #r Phe Thr Asn Ser                 1580  #               1585   #              1590 Trp Asn Ile Phe Asp Phe Val Val Val Ile Le #u Ser Ile Val Gly                 1595  #               1600   #              1605 Thr Val Leu Ser Asp Ile Ile Gln Lys Tyr Ph #e Phe Ser Pro Thr                 1610  #               1615   #              1620 Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gl #y Arg Ile Leu Arg                 1625  #               1630   #              1635 Leu Ile Arg Gly Ala Lys Gly Ile Arg Thr Le #u Leu Phe Ala Leu                 1640  #               1645   #              1650 Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gl #y Leu Leu Leu Phe                 1655  #               1660   #              1665 Leu Val Met Phe Ile Tyr Ser Ile Phe Gly Me #t Ala Asn Phe Ala                 1670  #               1675   #              1680 Tyr Val Lys Trp Glu Ala Gly Ile Asp Asp Me #t Phe Asn Phe Gln                 1685  #               1690   #              1695 Thr Phe Ala Asn Ser Met Leu Cys Leu Phe Gl #n Ile Thr Thr Ser                 1700  #               1705   #              1710 Ala Gly Trp Asp Gly Leu Leu Ser Pro Ile Le #u Asn Thr Gly Pro                 1715  #               1720   #              1725 Pro Tyr Cys Asp Pro Thr Leu Pro Asn Ser As #n Gly Ser Arg Gly                 1730  #               1735   #              1740 Asp Cys Gly Ser Pro Ala Val Gly Ile Leu Ph #e Phe Thr Thr Tyr                 1745  #               1750   #              1755 Ile Ile Ile Ser Phe Leu Ile Val Val Asn Me #t Tyr Ile Ala Ile                 1760  #               1765   #              1770 Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Gl #u Ser Thr Glu Pro                 1775  #               1780   #              1785 Leu Ser Glu Asp Asp Phe Asp Met Phe Tyr Gl #u Ile Trp Glu Lys                 1790  #               1795   #              1800 Phe Asp Pro Glu Ala Thr Gln Phe Ile Glu Ty #r Ser Val Leu Ser                 1805  #               1810   #              1815 Asp Phe Ala Asp Ala Leu Ser Glu Pro Leu Il #e Arg Ala Lys Pro                 1820  #               1825   #              1830 Asn Gln Ile Ser Leu Ile Asn Met Asp Leu Pr #o Met Val Ser Gly                 1835  #               1840   #              1845 Asp Arg Ile His Cys Met Asp Ile Leu Phe Al #a Phe Thr Lys Arg                 1850  #               1855   #              1860 Val Leu Gly Glu Ser Gly Glu Met Asp Ala Le #u Lys Ile Gln Met                 1865  #               1870   #              1875 Glu Glu Lys Phe Met Ala Ala Asn Pro Ser Ly #s Ile Ser Tyr Glu                 1880  #               1885   #              1890 Pro Ile Thr Thr Thr Leu Arg Arg Lys His Gl #u Glu Val Ser Ala                 1895  #               1900   #              1905 Met Val Ile Gln Arg Ala Phe Arg Arg His Le #u Leu Gln Arg Ser                 1910  #               1915   #              1920 Leu Lys His Ala Ser Phe Leu Phe Arg Gln Gl #n Ala Gly Ser Gly                 1925  #               1930   #              1935 Leu Ser Glu Glu Asp Ala Pro Glu Arg Glu Gl #y Leu Ile Ala Tyr                 1940  #               1945   #              1950 Val Met Ser Glu Asn Phe Ser Arg Pro Leu Gl #y Pro Pro Ser Ser                 1955  #               1960   #              1965 Ser Ser Ile Ser Ser Thr Ser Phe Pro Pro Se #r Tyr Asp Ser Val                 1970  #               1975   #              1980 Thr Arg Ala Thr Ser Asp Asn Leu Gln Val Ar #g Gly Ser Asp Tyr                 1985  #               1990   #              1995 Ser His Ser Glu Asp Leu Ala Asp Phe Pro Pr #o Ser Pro Asp Arg                 2000  #               2005   #              2010 Asp Arg Glu Ser Ile Val                 2015 (2) INFORMATION FOR SEQ ID NO: 3:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #3: ATGGCAAACT TCCTATTACC TCGG           #                   #                24 (2) INFORMATION FOR SEQ ID NO: 4:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #4: CACGATGGAC TCACGGTCCC TGTC           #                   #                24 (2) INFORMATION FOR SEQ ID NO: 5:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 3069 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: double           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #5: ATG GGG AAG GGG GTT GGA CGT GAT AAG TAT GA #G CCT GCA GCT GTT            #45 Met Gly Lys Gly Val Gly Arg Asp Lys Tyr Gl #u Pro Ala Ala Val 1                5   #                10   #                15 TCA GAA CAA GGT GAT AAA AAG GGC AAA AAG GG #C AAA AAA GAC AGG            #90 Ser Glu Gln Glu Asp Lys Lys Glu Lys Lys Gl #u Lys Lys Asp Arg                 20   #                25   #                30 GAC ATG GAT GAA CTG AAG AAA GAA GTT TCT AT #G GAT GAT CAT AAA          13 #5 Asp Met Asp Glu Leu Lys Lys Glu Val Ser Me #t Asp Asp His Lys                 35   #                40   #                45 CTT AGC CTT GAT GAA CTT CAT CGT AAA TAT GG #A ACA GAC TTG AGC          18 #0 Leu Ser Leu Asp Glu Leu His Arg Lys Tyr Gl #y Thr Asp Leu Ser                  50  #                 55  #                 60 CGG GGA TTA ACA TCT GCT CGT GCA GCT GAG AT #C CTG GCG CGA GAT          22 #5 Arg Gly Leu Thr Ser Ala Arg Ala Ala Glu Il #e Leu Ala Arg Asp                  65  #                 70  #                 75 GGT CCC AAC GCC CTC ACT CCC CCT CCC ACT AC #T CCT GAA TGG ATC          27 #0 Gly Pro Asn Ala Leu Thr Pro Pro Pro Thr Th #r Pro Glu Trp Ile                  80  #                 85  #                 90 AAG TTT TGT CGG CAG CTC TTT GGG GGG TTC TC #A ATG TTA CTG TGG          31 #5 Lys Phe Cys Arg Gln Leu Phe Gly Gly Phe Se #r Met Leu Leu Trp                  95  #                100  #                105 ATT GGA GCG ATT CTT TGT TTC TTG GCT TAT AG #C ATC CAA GCT GCT          36 #0 Ile Gly Ala Ile Leu Cys Phe Leu Ala Tyr Se #r Ile Gln Ala Ala                 110   #               115   #               120 ACA GAA GAG GAA CCT CAA AAC GAT AAT CTG TA #C CTG GGT GTG GTG          40 #5 Thr Glu Glu Glu Pro Gln Asn Asp Asn Leu Ty #r Leu Gly Val Val                 125   #               130   #               135 CTA TCA GCC GTT GTA ATC ATA ACT GGT TGC TT #C TCC TAC TAT CAA          45 #0 Leu Ser Ala Val Val Ile Ile Thr Gly Cys Ph #e Ser Tyr Tyr Gln                 140   #               145   #               150 GAA GCT AAA AGT TCA AAG ATC ATG GAA TCC TT #C AAA AAC ATG GTC          49 #5 Glu Ala Lys Ser Ser Lys Ile Met Glu Ser Ph #e Lys Asn Met Val                 155   #               160   #               165 CCT CAG CAA GCC CTT GTG ATT CGA AAT GGT GA #G AAA ATG AGC ATA          54 #0 Pro Gln Gln Ala Leu Val Ile Arg Asn Gly Gl #u Lys Met Ser Ile                 170   #               175   #               180 AAT GCG GAG GAA GTT GTG GTT GGG GAT CTG GT #G GAA GTA AAA GGA          58 #5 Asn Ala Glu Glu Val Val Val Gly Asp Lue Va #l Glu Val Lys Gly                 185   #               190   #               195 GGA GAC CGA ATT CCT GCT GAC CTC AGA ATC AT #A TCT GCA AAT GGC          63 #0 Gly Asp Arg Ile Pro Ala Asp Leu Arg Ile Il #e Ser Ala Asn Gly                 200   #               205   #               210 TGC AAG GTG GAT AAC TCC TCG CTC ACT GGT GA #A TCA GAA CCC CAG          67 #5 Cys Lys Val Asp Asn Ser Ser Leu Thr Gly Gl #u Ser Glu Pro Gln                 215   #               220   #               225 ACT AGG TCT CCA GAT TTC ACA AAT GAA AAC CC #C CTG GAG ACG AGG          72 #0 Thr Arg Ser Pro Asp Phe Thr Asn Glu Asn Pr #o Leu Glu Thr Arg                 230   #               235   #               240 AAC ATT GCC TTC TTT TCA ACA AAT TGT GTT GA #A GGC ACC GCA CGT          76 #5 Asn Ile Ala Phe Phe Ser Thr Asn Cys Val Gl #u Gly Thr Ala Arg                 245   #               250   #               255 GGT ATT GTT GTC TAC ACT GGG GAT CGC ACT GT #G ATG GGA AGA ATT          81 #0 Gly Ile Val Val Tyr Thr Gly Asp Arg Thr Va #l Met Gly Arg Ile                 260   #               265   #               270 GCC ACA CTT GCT TCT GGG CTG GAA GGA GGC CA #G ACC CCC ATT GCT          85 #5 Ala Thr Leu Ala Ser Gly Leu Glu Gly Gly Gl #n Thr Pro Ile Ala                 275   #               280   #               285 GCA GAA ATT GAA CAT TTT ATC CAC ATC ATC AC #G GGT GTG GCT GTG          90 #0 Ala Glu Ile Glu His Phe Ile His Ile Ile Th #r Gly Val Ala Val                 290   #               295   #               300 TTC CTG GGT GTG TCT TTC TTC ATC CTT TCT CT #C ATC CTT GAG TAC          94 #5 Phe Leu Gly Val Ser Phe Phe Ile Leu Ser Le #u Ile Leu Glu Tyr                 305   #               310   #               315 ACC TGG CTT GAG GCT GTC ATC TTC CTC ATC GG #T ATC ATC GTA GCC          99 #0 Thr Trp Leu Glu Ala Val Ile Phe Leu Ile Gl #y Ile Ile Val Ala                 320   #               325   #               330 AAT GTG CCG GAA GGT TTG CTG GCC ACT GTC AC #G GTC TGT CTG ACA         1035 Asn Val Pro Glu Gly Leu Leu Ala Thr Val Th #r Val Cys Leu Thr                 335   #               340   #               345 CTT ACT GCC AAA CGC ATG GCA AGG AAA AAC TG #C TTA GTG AAG AAC         1080 Leu Thr Ala Lys Arg Met Ala Arg Lys Asn Cy #s Leu Val Lys Asn                 350   #               355   #               360 TTA GAA GCT GTG GAG ACC TTG GGG TCC ACG TC #C ACC ATC TGC TCT         1125 Leu Glu Ala Val Glu Thr Leu Gly Ser Thr Se #r Thr Ile Cys Ser                 365   #               370   #               375 GAT AAA ACT GGA ACT CTG ACT CAG AAC CGG AT #G ACA GTG GCC CAC         1170 Asp Lys Thr Gly Thr Leu Thr Gln Asn Arg Me #t Thr Val Ala His                 380   #               385   #               390 ATG TGG TTT GAC AAT CAA ATC CAT GAA GCT GA #T ACG ACA GAG AAT         1215 Met Trp Phe Asp Asn Gln Ile His Glu Ala As #p Thr Thr Glu Asn                 395   #               400   #               405 CAG AGT GGT GTC TCT TTT GAC AAG ACT TCA GC #T ACC TGG CTT GCT         1260 Gln Ser Gly Val Ser Phe Asp Lys Thr Ser Al #a Thr Trp Leu Ala                 410   #               415   #               420 CTG TCC AGA ATT GCA GGT CTT TGT AAC AGG GC #A GTG TTT CAG GCT         1305 Leu Ser Arg Ile Ala Gly Leu Cys Asn Arg Al #a Val Phe Gln Ala                 425   #               430   #               435 AAC CAG GAA AAC CTA CCT ATT CTT AAG CGG GC #A GTT GCA GGA GAT         1350 Asn Gln Glu Asn Leu Pro Ile Leu Lys Arg Al #a Val Ala Gly Asp                 440   #               445   #               450 GCC TCT GAG TCA GCA CTC TTA AAG TGC ATA GA #G CTG TGC TGT GGT         1395 Ala Ser Glu Ser Ala Leu Leu Lys Cys Ile Gl #u Leu Cys Cys Gly                 455   #               460   #               465 TTC GTG AAG GAG ATG AGA GAA AGA TAC GCC AA #A ATC GTC GAG ATA         1440 Ser Val Lys Glu Met Arg Glu Arg Tyr Ala Ly #s Ile Val Glu Ile                 470   #               475   #               480 CCC TTC AAC TCC ACC AAC AAG TAC CAG TTG TC #T ATT CAT AAG AAC         1485 Pro Phe Asn Ser Thr Asn Lys Tyr Gln Leu Se #r Ile His Lys Asn                 485   #               490   #               495 CCC AAC ACA TCG GAG CCC CAA CAC CTG TTG GT #G ATG AAG GGC GCC         1530 Pro Asn Thr Ser Glu Pro Gln His Leu Leu Va #l Met Lys Gly Ala                 500   #               505   #               510 CCA GAA AGG ATC CTA GAC CGT TGC AGC TCT AT #C CTC CTC CAC GGC         1575 Pro Glu Arg Ile Leu Asp Arg Cys Ser Ser Il #e Leu Leu His Gly                 515   #               520   #               525 AAG GAG CAG CCC CTG GAT GAG GAG CTG AAA GA #C GCC TTT CAG AAC         1620 Lys Glu Gln Pro Leu Asp Glu Glu Leu Lys As #p Ala Phe Gln Asn                 530   #               535   #               540 GCC TAT TTG GAG CTG GGG GGC CTC GGA GAA CG #A GTC CTA GGT TTC         1665 Ala Tyr Leu Glu Leu Gly Gly Leu Gly Glu Ar #g Val Leu Gly Phe                 545   #               550   #               555 TGC CAC CTC TTT CTG CCA GAT GAA CAG TTT CC #T GAA GGG TTC CAG         1710 Cys His Leu Phe Leu Pro Asp Glu Gln Phe Pr #o Glu Gly Phe Gln                 560   #               565   #               570 TTT GAC ACT GAC GAT GTG AAT TTC CCT ATC GA #T AAT CTG TGC TTC         1755 Phe Asp Thr Asp Asp Val Asn Phe Pro Ile As #p Asn Leu Cys Phe                 575   #               580   #               585 GTT GGG CTC ATC TCC ATG ATT GAC CCT CCA CG #G GCG GCC GTT CCT         1800 Val Gly Leu Ile Ser Met Ile Asp Pro Pro Ar #g Ala Ala Val Pro                 590   #               595   #               600 GAT GCC GTG GGC AAA TGT CGA AGT GCT GGA AT #T AAG GTC ATC ATG         1845 Asp Ala Val Gly Lys Cys Arg Ser Aal Gly Il #e Lys Val Ile Met                 605   #               610   #               615 GTC ACA GGA GAC CAT CCA ATC ACA GCT AAA GC #T ATT GCC AAA GGT         1890 Val Thr Gly Asp His Pro Ile Thr Ala Lys Al #a Ile Ala Lys Gly                 620   #               625   #               630 GTG GGC ATC ATC TCA GAA GGC ATG GAG ACC GT #G GAA GAC ATT GCT         1935 Val Gly Ile Ile Ser Glu Gly Asn Glu Thr Va #l Glu Asp Ile Ala                 635   #               640   #               645 GCC CGC CTC AAC ATC CCA GTC AGC CAG GTG AA #C CCC AGG GAT GCC         1980 Ala Arg Leu Asn Ile Pro Val Ser Gln Val As #n Pro Arg Asp Ala                 650   #               655   #               660 AAG GCC TGC GTA GTA CAC GGC AGT GAT CTA AA #G GAC ATG ACC TCC         2025 Lys Ala Cys Val Val His Gly Ser Asp Leu Ly #s Asp Met Thr Ser                 665   #               670   #               675 GAG CAG CTG GAT GAC ATT TTG AAG TAC CAC AC #T GAG ATA GTG TTT         2070 Glu Glm Leu Asp Asp Ile Leu Lys Tyr His Th #r Glu Ile Val Phe                 680   #               685   #               690 GCC AGG ACC TCC CCT CAG CAG AAG CTC ATC AT #T GTG GAA GGC TGC         2115 Ala Arg Thr Ser Pro Gln Gln Lys Leu Ile Il #e Val Glu Gly Cys                 695   #               700   #               705 CAA AGA CAG GGT GCT ATC GTG GCT GTG ACT GG #T GAC GGT GTG AAT         2160 Gln Arg Gln Gly Ala Ile Val Ala Val Thr Gl #y Asp Gly Val Asn                 710   #               715   #               720 GAC TCT CCA GCT TTG AAG AAA GCA GAC ATT GG #G GTT GCT ATG GGG         2205 Asp Ser Pro Ala Leu Lys Lys Ala Asp Ile Gl #y Val Ala Met Gly                 725   #               730   #               735 ATT GCT GGC TCA GAT GTG TCC AAG CAA GCT GC #T GAC ATG ATT CTT         2250 Ile Ala Gly Ser Asp Val Ser Lys Gln Ala Al #a Asp Met Ile Leu                 740   #               745   #               750 CTG GAT GAC AAC TTT GCC TCA ATT GTG ACT GG #A GTA GAG GAA GGT         2295 Leu Asp Asp Asn Phe Ala Ser Ile Val Thr Gl #y Val Glu Glu Gly                 755   #               760   #               765 CGT CTG ATC TTT GAT AAC TTG AAG AAA TCC AT #T GCT TAT ACC TTA         2340 Arg Leu Ile Phe Asp Asn Leu Lys Lys Ser Il #e Ala Tyr Thr Leu                 770   #               775   #               780 ACC AGT AAC ATT CCC GAG ATC ACC CCG TTC CT #G ATA TTT ATT ATT         2385 Thr Ser Asn Ile Pro Glu Ile Thr Pro Phe Le #u Ile Phe Ile Ile                 785   #               790   #               795 GCA AAC ATT CCA CTA CCA CTG GGG ACT GTC AC #C ATC CTC TGC ATT         2430 Ala Asn Ile Pro Leu Pro Leu Gly Thr Val Th #r Ile Leu Cys Ile                 800   #               805   #               810 GAC TTG GGC ACT GAC ATG GTT CCT GCC ATC TC #C CTG GCT TAT GAG         2475 Asp Leu Gly Thr Asp Met Val Pro Ala Ile Se #r Leu Ala Tyr Glu                 815   #               820   #               825 CAG GCT GAG AGT GAC ATC ATG AAG AGA CAG CC #C AGA AAT CCC AAA         2520 Gln Ala Glu Ser Asp Ile Met Lys Arg Gln Pr #o Arg Asn Pro Lys                 830   #               835   #               840 ACA GAC AAA CTT GTG AAT GAG CGG CTG ATC AG #C ATG GCC TAT GGG         2565 Thr Asp Lys Leu Val Asn Glu Arg Leu Ile Se #r Met Ala Tyr Gly                 845   #               850   #               855 CAG ATT GGA ATG ATC CAG GCC CTG GGA GGC TT #C TTT ACT TAC TTT         2610 Gln Ile Gly Met Ile Gln Ala Leu Gly Gly Ph #e Phe Thr Tyr Phe                 860   #               865   #               870 GTG ATT CTG GCT GAG AAC GGC TTC CTC CCA AT #T CAC CTG TTG GGC         2655 Val Ile Leu Ala Glu Asn Gly Phe Leu Pro Il #e His Leu Leu Gly                 875   #               880   #               885 CTC CGA GTG GAC TGG GAT GAC CGC TGG ATC AA #C GAT GTG GAA GAC         2700 Leu Arg Val Asp Trp Asp Asp Arg Trp Ile As #n Asp Val Glu Asp                 890   #               895   #               900 AGC TAC GGG CAG CAG TGG ACC TAT GAG CAG AG #G AAA ATC GTG GAG         2745 Ser Tyr Gly Gln Gln Trp Thr Tyr Glu Gln Ar #g Lys Ile Val Glu                 905   #               910   #               915 TTC ACC TGC CAC ACA GCC TTC TTC GTC AGT AT #C GTG GTG GTG CAG         2790 Phe Thr Cys His Thr Ala Phe Phe Val Ser Il #e Val Val Val Gln                 920   #               925   #               930 TGG GCC GAC TTG GTC ATC TGT AAG ACC AGG AG #G AAT TCG GTC TTC         2835 Trp Ala Asp Leu Val Ile Cys Lys Thr Arg Ar #g Asn Ser Val Phe                 935   #               940   #               945 CAG CAG GGG ATG AAG AAC AAG ATC TTG ATA TT #T GGC CTC TTT GAA         2880 Gln Gln Gly Met Lys Asn Lys Ile Leu Ile Ph #e Gly Leu Phe Glu                 950   #               955   #               960 GAG ACA GCC CTG GCT GCT TTC CTT TCC TAC TG #C CCT GGA ATG GGT         2925 Glu Thr Ala Leu Ala Ala Phe Leu Ser Tyr Cy #s Pro Gly Met Gly                 965   #               970   #               975 GTT GCT CTT AGG ATG TAT CCC CTC AAA CCT AC #C TGG TGG TTC TGT         2970 Val Ala Leu Arg Met Tyr Pro Leu Lys Pro Th #r Trp Trp Phe Cys                 980   #               985   #               990 GCC TTC CCC TAC TCT CTT CTC ATC TTC GTA TA #T GAC GAA GTC AGA         3015 Ala Phe Pro Tyr Ser Leu Leu Ile Phe Val Ty #r Asp Glu Val Arg                 995   #               1000   #              1005 AAA CTC ATC ATC AGG CGA CGC CCT GGC GGC TG #G GTG GAG AAG GAA         3060 Lys Leu Ile Ile Arg Arg Arg Pro Gly Gly Tr #p Val Glu Lys Glu                 1010  #               1015   #              1020 ACC TAC TAT               #                   #                   #       3069 Thr Tyr Tyr (2) INFORMATION FOR SEQ ID NO: 6:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 1023 amino  #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: unknown     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #6: Met Gly Lys Gly Val Gly Arg Asp Lys Tyr Gl #u Pro Ala Ala Val  1                5  #                 10  #                 15 Ser Glu Gln Glu Asp Lys Lys Glu Lys Lys Gl #u Lys Lys Asp Arg                  20  #                 25  #                 30 Asp Met Asp Glu Leu Lys Lys Glu Val Ser Me #t Asp Asp His Lys                  35  #                 40  #                 45 Leu Ser Leu Asp Glu Leu His Arg Lys Tyr Gl #y Thr Asp Leu Ser                  50  #                 55  #                 60 Arg Gly Leu Thr Ser Ala Arg Ala Ala Glu Il #e Leu Ala Arg Asp                  65  #                 70  #                 75 Gly Pro Asn Ala Leu Thr Pro Pro Pro Thr Th #r Pro Glu Trp Ile                  80  #                 85  #                 90 Lys Phe Cys Arg Gln Leu Phe Gly Gly Phe Se #r Met Leu Leu Trp                  95  #                100  #                105 Ile Gly Ala Ile Leu Cys Phe Leu Ala Tyr Se #r Ile Gln Ala Ala                 110   #               115   #               120 Thr Glu Glu Glu Pro Gln Asn Asp Asn Leu Ty #r Leu Gly Val Val                 125   #               130   #               135 Leu Ser Ala Val Val Ile Ile Thr Gly Cys Ph #e Ser Tyr Tyr Gln                 140   #               145   #               150 Glu Ala Lys Ser Ser Lys Ile Met Glu Ser Ph #e Lys Asn Met Val                 155   #               160   #               165 Pro Gln Gln Ala Leu Val Ile Arg Asn Gly Gl #u Lys Met Ser Ile                 170   #               175   #               180 Asn Ala Glu Glu Val Val Val Gly Asp Leu Va #l Glu Val Lys Gly                 185   #               190   #               195 Gly Asp Arg Ile Pro Ala Asp Leu Arg Ile Il #e Ser Ala Asn Gly                 200   #               205   #               210 Cys Lys Val Asp Asn Ser Ser Leu Thr Gly Gl #u Ser Glu Pro Gln                 215   #               220   #               225 Thr Arg Ser Pro Asp Phe Thr Asn Glu Asn Pr #o Leu Glu Thr Arg                 230   #               235   #               240 Asn Ile Ala Phe Phe Ser Thr Asn Cys Val Gl #u Gly Thr Ala Arg                 245   #               250   #               255 Gly Ile Val Val Tyr Thr Gly Asp Arg Thr Va #l Met Gly Arg Ile                 260   #               265   #               270 Ala Thr Leu Ala Ser Gly Leu Glu Gly Gly Gl #n Thr Pro Ile Ala                 275   #               280   #               285 Ala Glu Ile Glu His Phe Ile His Ile Ile Th #r Gly Val Ala Val                 290   #               295   #               300 Phe Leu Gly Val Ser Phe Phe Ile Leu Ser Le #u Ile Leu Glu Tyr                 305   #               310   #               315 Thr Trp Leu Glu Ala Val Ile Phe Leu Ile Gl #y Ile Ile Val Ala                 320   #               325   #               330 Asn Val Pro Glu Gly Leu Leu Ala Thr Val Th #r Val Cys Leu Thr                 335   #               340   #               345 Leu Thr Ala Lys Arg Met Ala Arg Lys Asn Cy #s Leu Val Lys Asn                 350   #               355   #               360 Leu Glu Ala Val Glu Thr Leu Gly Ser Thr Se #r Thr Ile Cys Ser                 365   #               370   #               375 Asp Lys Thr Gly Thr Leu Thr Gln Asn Arg Me #t Thr Val Ala His                 380   #               385   #               390 Met Trp Phe Asp Asn Gln Ile His Glu Ala As #p Thr Thr Glu Asn                 395   #               400   #               405 Gln Ser Gly Val Ser Phe Asp Lys Thr Ser Al #a Thr Trp Leu Ala                 410   #               415   #               420 Leu Ser Arg Ile Ala Gly Leu Cys Asn Arg Al #a Val Phe Gln Ala                 425   #               430   #               435 Asn Gln Glu Asn Leu Pro Ile Leu Lys Arg Al #a Val Ala Gly Asp                 440   #               445   #               450 Ala Ser Glu Ser Ala Leu Leu Lys Cys Ile Gl #u Leu Cys Cys Gly                 455   #               460   #               465 Ser Val Lys Glu Met Arg Glu Arg Tyr Ala Ly #s Ile Val Glu Ile                 470   #               475   #               480 Pro Phe Asn Ser Thr Asn Lys Tyr Gln Leu Se #r Ile His Lys Asn                 485   #               490   #               495 Pro Asn Thr Ser Glu Pro Gln His Leu Leu Va #l Met Lys Gly Ala                 500   #               505   #               510 Pro Glu Arg Ile Leu Asp Arg Cys Ser Ser Il #e Leu Leu His Gly                 515   #               520   #               525 Lys Glu Gln Pro Leu Asp Glu Glu Leu Lys As #p Ala Phe Gln Asn                 530   #               535   #               540 Ala Tyr Leu Glu Leu Gly Gly Leu Gly Glu Ar #g Val Leu Gly Phe                 545   #               550   #               555 Cys His Leu Phe Leu Pro Asp Glu Gln Phe Pr #o Glu Gly Phe Gln                 560   #               565   #               570 Phe Asp Thr Asp Asp Val Asn Phe Pro Ile As #p Asn Leu Cys Phe                 575   #               580   #               585 Val Gly Leu Ile Ser Met Ile Asp Pro Pro Ar #g Ala Ala Val Pro                 590   #               595   #               600 Asp Ala Val Gly Lys Cys Arg Ser Ala Gly Il #e Lys Val Ile Met                 605   #               610   #               615 Val Thr Gly Asp His Pro Ile Thr Ala Lys Al #a Ile Ala Lys Gly                 620   #               625   #               630 Val Gly Ile Ile Ser Glu Gly Asn Glu Thr Va #l Glu Asp Ile Ala                 635   #               640   #               645 Ala Arg Leu Asn Ile Pro Val Ser Gln Val As #n Pro Arg Asp Ala                 650   #               655   #               660 Lys Ala Cys Val Val His Gly Ser Asp Leu Ly #s Asp Met Thr Ser                 665   #               670   #               675 Glu Gln Leu Asp Asp Ile Leu Lys Tyr His Th #r Glu Ile Val Phe                 680   #               685   #               690 Ala Arg Thr Ser Pro Gln Gln Lys Leu Ile Il #e Val Glu Gly Cys                 695   #               700   #               705 Gln Arg Gln Gly Ala Ile Val Ala Val Thr Gl #y Asp Gly Val Asn                 710   #               715   #               720 Asp Ser Pro Ala Leu Lys Lys Ala Asp Ile Gl #y Val Ala Met Gly                 725   #               730   #               735 Ile Ala Gly Ser Asp Val Ser Lys Gln Ala Al #a Asp Met Ile Leu                 740   #               745   #               750 Leu Asp Asp Asn Phe Ala Ser Ile Val Thr Gl #y Val Glu Glu Gly                 755   #               760   #               765 Arg Leu Ile Phe Asp Asn Leu Lys Lys Ser Il #e Ala Tyr Thr Leu                 770   #               775   #               780 Thr Ser Asn Ile Pro Glu Ile Thr Pro Phe Le #u Ile Phe Ile Ile                 785   #               790   #               795 Ala Asn Ile Pro Leu Pro Leu Gly Thr Val Th #r Ile Leu Cys Ile                 800   #               805   #               810 Asp Leu Gly Thr Asp Met Val Pro Ala Ile Se #r Leu Ala Tyr Glu                 815   #               820   #               825 Gln Ala Glu Ser Asp Ile Met Lys Arg Gln Pr #o Arg Asn Pro Lys                 830   #               835   #               840 Thr Asp Lys Leu Val Asn Glu Arg Leu Ile Se #r Met Ala Tyr Gly                 845   #               850   #               855 Gln Ile Gly Met Ile Gln Ala Leu Gly Gly Ph #e Phe Thr Tyr Phe                 860   #               865   #               870 Val Ile Leu Ala Glu Asn Gly Phe Leu Pro Il #e His Leu Leu Gly                 875   #               880   #               885 Leu Arg Val Asp Trp Asp Asp Arg Trp Ile As #n Asp Val Glu Asp                 890   #               895   #               900 Ser Tyr Gly Gln Gln Trp Thr Tyr Glu Gln Ar #g Lys Ile Val Glu                 905   #               910   #               915 Phe Thr Cys His Thr Ala Phe Phe Val Ser Il #e Val Val Val Gln                 920   #               925   #               930 Trp Ala Asp Leu Val Ile Cys Lys Thr Arg Ar #g Asn Ser Val Phe                 935   #               940   #               945 Gln Gln Gly Met Lys Asn Lys Ile Leu Ile Ph #e Gly Leu Phe Glu                 950   #               955   #               960 Glu Thr Ala Leu Ala Ala Phe Leu Ser Tyr Cy #s Pro Gly Met Gly                 965   #               970   #               975 Val Ala Leu Arg Met Tyr Pro Leu Lys Pro Th #r Trp Trp Phe Cys                 980   #               985   #               990 Ala Phe Pro Tyr Ser Leu Leu Ile Phe Val Ty #r Asp Glu Val Arg                 995   #               1000   #              1005 Lys Leu Ile Ile Arg Arg Arg Pro Gly Gly Tr #p Val Glu Lys Glu                 1010  #               1015   #              1020 Thr Tyr Tyr (2) INFORMATION FOR SEQ ID NO: 7:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 909 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: double           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #7: ATG GCC CGC GGG AAA GCC AAG GAG GAG GGC AG #C TGG AAG AAA TTC            #45 Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Se #r Trp Lys Lys Phe  1                5  #                 10  #                 15 ATC TGG AAC TCA GAG AAG AAG GAG TTT CTG GG #C AGG ACC GGT GGC            #90 Ile Trp Asn Ser Glu Lys Lys Glu Phe Leu Gl #y Arg Thr Gly Gly                  20  #                 25  #                 30 AGT TGG TTT AAG ATC CTT CTA TTC TAC GTA AT #A TTT TAT GGC TGC          13 #5 Ser Trp Phe Lys Ile Leu Leu Phe Tyr Val Il #e Phe Tyr Gly Cys                  35  #                 40  #                 45 CTG GCT GGC ATC TTC ATC GGA ACC ATC CAA GT #G ATG CTG CTC ACC          18 #0 Leu Ala Gly Ile Phe Ile Gly Thr Ile Gln Va #l Met Leu Leu Thr                  50  #                 55  #                 60 ATC AGT GAA TTT AAG CCC ACA TAT CAG GAC CG #A GTG GCC CCG CCA          22 #5 Ile Ser Glu Phe Lys Pro Thr Tyr Gln Asp Ar #g Val Ala Pro Pro                  65  #                 70  #                 75 GGA TTA ACA CAG ATT CCT CAG ATC CAG AAG AC #T GAA ATT TCC TTT          27 #0 Gly Leu Thr Gln Ile Pro Gln Ile Gln Lys Th #r Glu Ile Ser Phe                  80  #                 85  #                 90 CGT CCT AAT GAT CCC AAG AGC TAT GAG GCA TA #T GTA CTG AAC ATA          31 #5 Arg Pro Asn Asp Pro Lys Ser Tyr Glu Ala Ty #r Val Leu Asn Ile                  95  #                100  #                105 GTT AGG TTC CTG GAA AAG TAC AAA GAT TCA GC #C CAG AGG GAT GAC          36 #0 Val Arg Phe Leu Glu Lys Tyr Lys Asp Ser Al #a Gln Arg Asp Asp                 110   #               115   #               120 ATG ATT TTT GAA GAT TGT GGC GAT GTG CCC AG #T GAA CCG AAA GAA          40 #5 Met Ile Phe Glu Asp Cys Gly Asp Val Pro Se #r Glu Pro Lys Glu                 125   #               130   #               135 CGA GGA GAC TTT AAT CAT GAA CGA GGA GAG CG #A AAG GTC TGC AGA          45 #0 Arg Gly Asp Phe Asn His Glu Arg Gly Glu Ar #g Lys Val Cys Arg                 140   #               145   #               150 TTC AAG CTT GAA TGG CTG GGA AAT TGC TCT GG #A TTA AAT GAT GAA          49 #5 Phy Lys Leu Glu Trp Leu Gly Asn Cys Ser Gl #y Leu Asn Asp Glu                 155   #               160   #               165 ACT TAT GGC TAC AAA GAG GGC AAA CCG TGC AT #T ATT ATA AAG CTC          54 #0 Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Il #e Ile Ile Lys Leu                 170   #               175   #               180 AAC CGA GTT CTA GGC TTC AAA CCT AAG CCT CC #C AAG AAT GAG TCC          58 #5 Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pr #o Lys Asn Glu Ser                 185   #               190   #               195 TTG GAG ACT TAC CCA GTG ATG AAG TAT AAC CC #A AAT GTC CTT CCC          63 #0 Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pr #o Asn Val Leu Pro                 200   #               205   #               210 GTT CAG TGC ACT GGC AAG CGA GAT GAA GAT AA #G GAT AAA GTT GGA          67 #5 Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Ly #s Asp Lys Val Gly                 215   #               220   #               225 AAT GTG GAG TAT TTT GGA CTG GGC AAC TCC CC #T GGT TTT CCT CTG          72 #0 Asn Val Glu Tyr Phe Gly Leu Gly Asn Ser Pr #o Gly Phe Pro Leu                 230   #               235   #               240 CAG TAT TAT CCG TAC TAT GGC AAA CTC CTG CA #G CCC AAA TAC CTG          76 #5 Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gl #n Pro Lys Tyr Leu                 245   #               250   #               255 CAG CCC CTG CTG GCC GTA CAG TTC ACC AAT CT #T ACC ATG GAC ACT          81 #0 Gln Pro Leu Leu Ala Val Gln Phe Thr Asn Le #u Thr Met Asp Thr                 260   #               265   #               270 GAA ATT CGC ATA GAG TGT AAG GCG TAC GGT GA #G AAC ATT GGG TAC          85 #5 Glu Ile Arg Ile Glu Cys Lys Ala Tyr Gly Gl #u Asn Ile Gly Tyr                 275   #               280   #               285 AGT GAG AAA GAC CGT TTT CAG GGA CGT TTT GA #T GTA AAA ATT GAA          90 #0 Ser Glu Lys Asp Arg Phe Gln Gly Arg Phe As #p Val Lys Ile Glu                 290   #               295   #               300 GTT AAG AGC               #                   #                   #        909 Val Lys Ser (2) INFORMATION FOR SEQ ID NO: 8:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 303 amino  #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: unknown     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #8: Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Se #r Trp Lys Lys Phe 1               5    #                10   #                15 Ile Trp Asn Ser Glu Lys Lys Glu Phe Leu Gl #y Arg Thr Gly Gly                 20   #                25   #                30 Ser Trp Phe Lys Ile Leu Leu Phe Tyr Val Il #e Phe Tyr Gly Cys                 35   #                40   #                45 Leu Ala Gly Ile Phe Ile Gly Thr Ile Gln Va #l Met Leu Leu Thr                 50   #                55   #                60 Ile Ser Glu Phe Lys Pro Thr Tyr Gln Asp Ar #g Val Ala Pro Pro                 65   #                70   #                75 Gly Leu Thr Gln Ile Pro Gln Ile Gln Lys Th #r Glu Ile Ser Phe                 80   #                85   #                90 Arg Pro Asn Asp Pro Lys Ser Tyr Glu Ala Ty #r Val Leu Asn Ile                 95   #                100  #                105 Val Arg Phe Leu Glu Lys Tyr Lys Asp Ser Al #a Gln Arg Asp Asp                 110   #               115   #               120 Met Ile Phe Glu Asp Cys Gly Asp Val Pro Se #r Glu Pro Lys Glu                 125   #               130   #               135 Arg Gly Asp Phe Asn His Glu Arg Gly Glu Ar #g Lys Val Cys Arg                 140   #               145   #               150 Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser Gl #y Leu Asn Asp Glu                 155   #               160   #               165 Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Il #e Ile Ile Lys Leu                 170   #               175   #               180 Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pr #o Lys Asn Glu Ser                 185   #               190   #               195 Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pr #o Asn Val Leu Pro                 200   #               205   #               210 Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Ly #s Asp Lys Val Gly                 215   #               220   #               225 Asn Val Glu Tyr Phe Gly Leu Gly Asn Ser Pr #o Gly Phe Pro Leu                 230   #               235   #               240 Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gl #n Pro Lys Tyr Leu                 245   #               250   #               255 Gln Pro Leu Leu Ala Val Gln Phe Thr Asn Le #u Thr Met Asp Thr                 260   #               265   #               270 Glu Ile Arg Ile Glu Cys Lys Ala Tyr Gly Gl #u Asn Ile Gly Tyr                 275   #               280   #               285 Ser Glu Lys Asp Arg Phe Gln Gly Arg Phe As #p Val Lys Ile Glu                 290   #               295   #               300 Val Lys Ser (2) INFORMATION FOR SEQ ID NO: 9:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #9: ATGGGGAAGG GGGTTGGACG TGAT           #                   #                24 (2) INFORMATION FOR SEQ ID NO: 10:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #10: ATAGTAGGTT TCCTTCTCCA CCCA           #                   #                24 (2) INFORMATION FOR SEQ ID NO: 11:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #11: ATGGCCCGCG GGAAAGCCAA GGAG           #                   #                24 (2) INFORMATION FOR SEQ ID NO: 12:      (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 24 bases           (B) TYPE: nucleic acid           (C) STRANDEDNESS: single           (D) TOPOLOGY: linear     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #12: GCTCTTAACT TCAATTTTTA CATC           #                   #                24 

What is claimed is:
 1. An implantable system for pacing a patient's heart and for delivering a predetermined genetic material to cells adjacent to a pacing electrode positioned in said patient's heart, comprising: a supply of genetic material comprising cells containing DNA or RNA encoding an ion channel protein; a catheter, said catheter having proximal and distal ends, a lumen through at least a part thereof and connecting to said distal end, a pacing electrode positioned at said distal end for engaging said patient's heart wall, said electrode having a channel therethrough in communication with said lumen, and a conductor connecting said proximal end to said electrode, a pulse generator connected electrically to said conductor at said catheter proximal end for delivering pace pulses to said electrode, reservoir means for holding said supply of genetic material, and delivery means for delivering said genetic material from said reservoir to said lumen, whereby said material passes through said lumen and said channel to said heart wall.
 2. The implantable system of claim 1, wherein said reservoir is mounted in said pulse generator.
 3. The implantable system of claim 1, wherein said delivery means is passive.
 4. The implantable system of claim 1, wherein said delivery means comprises a pump.
 5. The implantable system of claim 1, wherein said electrode is substantially concentric with respect to the catheter axis, and the channel passes through the center of said electrode.
 6. The system as described in claim 1, further comprising: control means for controlling operation of said delivery means to deliver respective said doses.
 7. The implantable delivery system of claim 1, wherein said control means comprises initiating means for initiating delivery of said genetic material, said initiating means comprising an external programmer.
 8. The implantable delivery system of claim 1, wherein said control means comprises automatic means for automatically initiating delivery of said genetic material. 